AU749658B2 - Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting beta-amyloid peptide release and/or its synthesis by use of such compounds - Google Patents

Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting beta-amyloid peptide release and/or its synthesis by use of such compounds Download PDF

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AU749658B2
AU749658B2 AU57007/98A AU5700798A AU749658B2 AU 749658 B2 AU749658 B2 AU 749658B2 AU 57007/98 A AU57007/98 A AU 57007/98A AU 5700798 A AU5700798 A AU 5700798A AU 749658 B2 AU749658 B2 AU 749658B2
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Australia
Prior art keywords
dihydro
amino
methyl
alaninyl
benzodiazepin
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AU57007/98A
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AU5700798A (en
AU749658C (en
Inventor
James E Audia
Thomas C. Britton
Cynthia L. Cwi
Bruce A Dressman
James J Droste
Stephen Freedman
Steven S. Henry
Varghese John
Lee H. Latimer
Thomas E Mabry
Stacey L. Mcdaniel
Jeffrey Neitz
Jeffrey S Nissen
Michael A. Pleiss
Warren J. Porter
Jon K. Reel
William Leonard Scott
Russell D. Stucky
Eugene D. Thorsett
Jay S. Tung
Jing Wu
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Elan Pharmaceuticals LLC
Eli Lilly and Co
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Elan Pharmaceuticals LLC
Eli Lilly and Co
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Publication of AU5700798A publication Critical patent/AU5700798A/en
Publication of AU749658B2 publication Critical patent/AU749658B2/en
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Description

CYCLOALKYL, LACTAM, LACTONE AND RELATED COMPOUNDS, PHARMACEUTICAL COMPOSITIONS
COMPRISING
SAME, AND METHODS FOR INHIBITING 8-AMYLOID
PEPTIDE
RELEASE AND/OR ITS SYNTHESIS BY USE OF SUCH COMPOUNDS SField of the Invention .*This invention relates to compounds which inhibit -amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating :Alzheimer's disease.
References The following publications, patents and patent applications are cited in this application as superscript numbers: .0 a Glenner, et al., Biochem. Biophys. Res. Commun., 120:885-890 (1984) U.S. Patent No. 4,666,829 Selkoe, Neuron, 6:487-498 (1991) Goate, et al., Nature, 349:704-706 (1990) 520 Chartier Harlan, et al., Nature, 353:844-846 (1989) 20 1 ;6 Murrell, et al., Science, 254:97-99 (1991) WO 98/28268 PCT/US97/22986 2-- 7 Mullan, et al., Nature Genet., 1:345-347 (1992) 8 Schenk, et al., International Patent Application Publication No.
WO 94/10569, "Methods and Compositions for the Detection of Soluble 0-Amyloid Peptide", published 11 May 1994 9 Selkoe, Scientific American, "Amyloid Protein and Alzheimer's Disease", pp. 2-8, November, 1991 o1 Tetrahedron Letters, 34(48), 7685 (1993) Losse, et al., Tetrahedron, 27:1423-1434 (1971) 12 Citron, et al., Nature, 360:672-674 (1992) 13 Hansen, et al., J. Immun. Meth., 119:203-210 (1989) 14 U.S. Patent No. 3,598,859 15 Ogliaruso and Wolfe, Synthesis of Lactones and Lactams, Patai, et al. Editor, J. Wiley Sons, New York, New York, USA, pp.
1085 et seq. (1993).
16 Ugi, et al., Tetrahedron, 52(35):11657-11664 (1996) 17 Blade-Font, Tetrahedron Lett., 21:2443 (1980).
18 Freidinger, et al., J. Org. Chem., 47:104-109 (1982) 1 9 Semple, et al., J. Med. Chem., 39:4531-4536 (1996).
Holladay, et al., J. Org. Chem., 56:3900-3905 (1991).
21 Donaruma, et al., Organic Reactions, 11:1-156 (1960) 22 Wolff, Organic Reactions, 3:307-336 (1946) 23 Krow, et al., J. Org. Chem., 61:5574-5580 (1996) 24 Tetrahedron, 35:2433 (1979) Gracias, et al., J. Am. Chem. Soc., 117:8047-8048 (1995) 26 Milligan, et al., J. Am. Chem. Soc., 117:10449-10459 (1995) 27 Miller, et al., J. Am. Chem. Soc., 118:9606-9614 (1996) WO 98/28268 PCT/US97/22986 3-- 28 March, Advanced Organic Chemistry, Reaction Mechanisms and Structure, 2nd Edition, McGraw-Hill Book Company, New York, New York, USA (1977) 29 Colombo; et al., Tetrahedron Lett., 35(23):4031-4034 (1994) Rogriguez, et al., Tetrahedron, 52:7727-7736 (1996) 31 Parsons, et al., Biochem. Biophys. Res. Comm., 117:108-113 (1983) 32 Watthey, et al., J. Med. Chem., 28:1511-1516 (1985) 33 Armstrong, et al., Tetrahedron Lett., 35:3239 (1994) 34 King, et al., J. Org. Chem., 58:3384 (1993).
Hu, et al., Tetrahedron Lett., 36(21):3659-3662 (1995).
36 Wada, et al., Bull. Chem. Soc. Japan, 46:2833-2835 (1973) 37 Gaetzi, Chem. Abs., 66:28690m 38 Wheeler, et al., Organic Syntheses, Coll. Vol. VI, p. 840 39 J. Med. Chem., 28(12): 1886 (1985) Brenner, et al., U.S. Patent No. 2,938,029 4 1 Evans, et al., J. Am. Chem. Soc., 112:4011-4030 (1990) 42 Micouin, et al., Tetrahedron, 52:7719-7726 (1996) 43 Butcher, et al., Tetrahedron Lett., 37(37):6685-6688 (1996) 44 M.L. Reupple, et al., J. Am. Chem. Soc., 93:7021 et seq. (1971) P.A.S. Smith, Organic Reactions, 3:337-449 (1946) 46 K. Orito, et al., Tetrahedron, 36:1017-1021 (1980) 47 Krimm, Chem. Ber., 91:1057 (1958) 48 Suda, et al., J. Chem. Soc. Chem Comm., 949-950, (1994) 49 Barton, et al., J. Chem. Soc., 1764-1767 (1975) WO W828268 P~r[US97/22986 4-- Kitagawa, et al., J. Am. Chem. Soc., 117:5169-5178 (1975) 51 Akhatar, et al., J. Org. Chem., 55:5222-5225 (1990) 52 Nedenskov, et al., Adta Chem. Scand_, 12:1405-1410 (1958) 53 Sakakida, et al., Bull. Chem. Soc. Japan, 44:478-480 (1971) 54 Hoffman, et al., Tet. Lett., 30:4207-4210 (1989) Vedejs, et al., Tel. Lett_, 33:3261-3264 (1992) 56 van der Steen, et al., Tetrahedron, 47, 7503-7524 (1991) 57 Hart, et al., Chem Rev_, 89:1447-1465 (1989) 58 Lowe, et al., Bioorg. Med. Chem. Let_. 4:2877-2882 (1994) 59 McKennis, Jr., et al., J. Org. Chem., 28:383-387 (1963) Shirota, et al., J. Med. Chem. 20:1623-1627 (1977) 61 Overberger, et al., J. Am. Chem. Soc., 85:3431 (1963) 62 Herschmann, Helv. Chim. Acta, 32:2537 (1949) 63 Overberger, et al., Macromolecules, 1:1 (1968) 64 Busacca, et al., Tet. Lett., 33:165-168 (1992) Croisier, et al., U.S. Patent No. 4,080,449 66 J.A. Robi, et al., Tetrahedron Lett., 36(10):1593-1596 (1995) 67 Flynn, et al., J. Med. Chem_, 36:2420-2423 (1993) 68 Orito, et al., Tetrahedron, 36: 1017-1021 (1980) 69 Kawase, et al., J. Org. Chem., 54:3394-3403 (1989) Lowe, et al., J. Med. Chem., 37:3789-3811 (1994) 71 Robi, et al., Bioorg. Med. Chem. Lett_, 4:1789-1794 (1994) 72 Skiles, et al., Bioorg. Med. Chem. Lett_, 3:773-778 (1993) WO 98/28268 PCTIUS97122986 73 Grunewald, et al., J. Med. Chem_, 39(18):3539 (1996) 74 Thomas, et al., J. Chem. Soc., Perkin 11, 747 (1986) 5 Warshawsky, et al., Bioorg. Med. Chem. Lett., 6:957-962 (1996) 76 Ben-Ishai, et al., Tetrahedron, 43:439-450 (1987) 77 van Niel et al., Bioorg. Med. Chem. Lett., 5:1421-1426 (1995) 78 Kawase, et al., J. Org. Chem., 54:3394-3403 (1989) 79 Edwards, et al., Can. Chem. 49:1648-1658 (1971) 80 Milligan, et al., J. Am. Chem. Soc., 117:10449-10459 (1995) 81 Curran et al., Tet. Lett., 36:191-194 (1995) 82 Slusarchyk, et al., Bioorg. Med. Chem. Lett., 5:753-758 (1995) 83 Wyvratt, et al., Eur. Pat. Appi. 61187 (1982) 84 Comnille, et al., J1. Am. Chem. Soc., 117:909-917 (1995) 85 Kolc, Coll. Czech. Chem. Comm. 34:630 (1969) 86 Dickerman, et al., J. Org. Chem., 14:530 (1949) 87 Dickerman, et al., Org. Chem_, 20:206 (1955) 88 Dickerman, et al., J1. Org. Chem_, 19:1855 (1954) 89 Hoffman, et al., J. Org. Chem_, 27:3565 (1962) 90 Wasserman, et al., J. Am. Chem. Soc., 103:461-2 (1981) 91 Crombie, et al., Tetrahedron Lett_, 27(42):5151-5154 (1986) 92 Yokoo, et al., Bull, Chem. Soc. Jap., 2:631 (1956) 93 Burkholder, et al., Biog. .Med. Chem. Lett_, 2:231 (1993) 94 Karanewsky, U.S. Patent No. 4,460,579 95 Kametani, et al., Heterocycles, 9:831-840 (1978) WO 98/28268 PCT/US97/22986 6-- 96 Yanganasawa, et al., J. Med. Chem., 30:1984-1991 (1987) 97 J. Das et al., Biorg. Med. Chem. Lett., 4:2193-2198 (1994) All of the above publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.
State of the Art Alzheimer's Disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability that gradually leads to profound mental deterioration and ultimately death. AD is a very common cause of progressive mental failure (dementia) in aged humans and is believed to represent the fourth most common medical cause of death in the United States. AD has been observed in races and ethnic groups worldwide and presents a major present and future public health problem. The disease is currently estimated to affect about two to three million individuals in the United States alone. AD is at present incurable. No treatment that effectively prevents AD or reverses its symptoms and course is currently known.
The brains of individuals with AD exhibit characteristic lesions termed senile (or amyloid) plaques, amyloid angiopathy (amyloid deposits in blood vessels) and neurofibrillary tangles. Large numbers of these lesions, particularly amyloid plaques and neurofibrillary tangles, are generally found in several areas of the human brain important for memory and cognitive function in patients with AD. Smaller numbers of these lesions in a more restrictive anatomical distribution are also found in the brains of most aged humans who do not have clinical AD. Amyloid plaques and amyloid angiopathy also characterize the brains of individuals with Trisomy 21 (Down's Syndrome) and Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type WO 98/28268 PCTIUS97/22986 7 (HCHWA-D). At present, a definitive diagnosis of AD usually requires observing the aforementioned lesions in the brain tissue of patients who have died with the disease or, rarely, in small biopsied samples of brain tissue taken during an invasive neurosurgical procedure.
The principal chemical constituent of the amyloid plaques and vascular amyloid deposits (amyloid angiopathy) characteristic of AD and the other disorders mentioned above is an approximately 4.2 kilodalton (kD) protein of about 39-43 amino acids designated the 0-amyloid peptide (3AP) or sometimes Af, AOP or 3/A4. 1-Amyloid peptide was first purified and a partial amino acid sequence was provided by Glenner, et al.' The isolation procedure and the sequence data for the first 28 amino acids are described in U.S. Patent No.
4,666,8292.
Molecular biological and protein chemical analyses have shown that the 0-amyloid peptide is a small fragment of a much larger precursor protein termed the amyloid precursor protein (APP), that is normally produced by cells in many tissues of various animals, including humans. Knowledge of the structure of the gene encoding APP has demonstrated that 1-amyloid peptide arises as a peptide fragment that is cleaved from APP by protease enzyme(s).
The precise biochemical mechanism by which the 3-amyloid peptide fragment is cleaved from APP and subsequently deposited as amyloid plaques in the cerebral tissue and in the walls of the cerebral and meningeal blood vessels is currently unknown.
Several lines of evidence indicate that progressive cerebral deposition of O-amyloid peptide plays a seminal role in the pathogenesis of AD and can precede cognitive symptoms by years or decades. See, for example, Selkoe 3 The most important line of evidence is the discovery that missense DNA mutations at amino acid 717 of the 770-amino acid isoform of APP can be found in affected members but not unaffected members of several families with WO 98/28268 PCT/US97/22986 -8a genetically determined (familial) form of AD (Goate, et al.
4 Chartier Harlan, et al.
5 and Murrell, et al.
6 and is referred to as the Swedish variant. A double mutation changing lysine 5 95 -methionine' 96 to asparagine 59 5 -leucine 596 (with reference to the 695 isoform) found in a Swedish family was reported in 1992 (Mullan, et al.
7 Genetic linkage analyses have demonstrated that these mutations, as well as certain other mutations in the APP gene, are the specific molecular cause of AD in the affected members of such families. In addition, a mutation at amino acid 693 of the 770-amino acid isoform of APP has been identified as the cause of the 0-amyloid peptide deposition disease, HCHWA-D, and a change from alanine to glycine at amino acid 692 appears to cause a phenotype that resembles AD is some patients but HCHWA-D in others. The discovery of these and other mutations in APP in genetically based cases of AD prove that alteration of APP and subsequent deposition of its 0-amyloid peptide fragment can cause AD.
Despite the progress which has been made in understanding the underlying mechanisms of AD and other 0-amyloid peptide related diseases, there remains a need to develop methods and compositions for treatment of the disease(s). Ideally, the treatment methods would advantageously be based on drugs which are capable of inhibiting 0-amyloid peptide release and/or its synthesis in vivo.
SUMMARY OF THE INVENTION This invention is directed to the discovery of a class of compounds which inhibit 0-amyloid peptide release and/or its synthesis and, therefore, are useful in the prevention of AD in patients susceptible to AD and/or in the treatment of patients with AD in order to inhibit further deterioration in their condition. The class of compounds having the described properties are defined by formula I below: 9
WW
RI 0Z NH C(H) m n
C
11
X
wherein R' is selected from the group consisting of alkyl, alkenyl.
alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic; W, together with forms a cycloalkyl, cycloalkenyl, S. heterocyclic, substituted cycloalkyl, or substituted cycloalkenyl group wherein ~each of said cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl or 25 substituted cycloalkenyl group is optionally fused to form a bi- or multi-fused ring system (preferably no more than 5 fused rings) with one or more ring structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group which, in turn, each of such ring structures are optionally substituted with 1 to 4 substituents selected from the 30 group consisting of hydroxyl, halo, alkoxy, substituted alkoxy, thioalkoxy, .a substituted thioalkoxy, nitro, cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, Nalkylamino, N,N-dialkylamino, N-substituted alkylamino, N-alkyl N-substituted alkylamino, N,N-disubstituted alkylamino, -NHC(O)R 4
-NHSO
2
-C(O)NH,,
-C(O)NHR
4
-C(O)NR
4
R
4
-S(O)R
4
-S(O),R
4
-S(O),NHR
4 and -S(O)2NR 4
R
4 where each R 4 is independently selected from the group consisting of alkyl, ,RAL substituted alkyl, or aryl; T- X is selected from the group consisting of oxo thiooxo -0 L hydroxyl thiol and hydro Y is represented by the formula: R2 /CH
/NH
11 0 wherein each R: is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynvl, cycloalkyl, aryl, heteroaryl and heterocyclic; Z is represented by the formula where T is selected from the group consisting of a bond covalently linking R' to oxygen, 20 sulfur, -NR' where R S is hydrogen, acyl, alkyl, aryl or heteroaryl group; X' is hydrogen, hydroxy or fluoro, X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group; with the proviso that when T is oxygen, sulfur or NR 5 then X' and X" are each hydrogen; mis n is an integer equal to 0, 1 or 2; p is an integer equal to 0 or 1 such that when p is zero, the ring defined by W and is unsaturated at the carbon atom of ring attachment to Y and when p is one, the ring is saturated at the carbon atom of ring attachment to Y, with the following provisos: A. when R' is 3 ,5-difluorophenyl,
R
2 is Z is n is 1, and p is 1, then W, together with >CH and does not form a 2-(S)-indanol group; 11 B. when R' is phenyl, R 2 is -CH- 3 Z is -CHC(Oy- n is 1, and p is 1. then W, together with CH and C does not form a trans-2hydroxy-cyclobex I -yl group; C. when R' is phenyl, Z is n is 0, and P is 1, then W, together with >CH and does not form a gamma-buiyrolaccone group or a 5,5-d inethylI gamma- buyrolactone group; D. when R' is phenyl, Z is n is 0, and p is 1, then W, together with >CH and does not iorm a e-caprolactan group; E. when R' is cyclopropyl, RI is -Cl- 3 Z is 11 is 1.
and p is 1, then W, together with C14 and C does not form an Nmethylcaprolactam group; F. when R' is 4 -chlorobenzoyiC2- R' is -CH 3 Z is -CH-IC n is 1. and p is 1, then W, together with CH- and C= X, does not form an 2, 3-dihydro- 1 -methyl-5-phenyl -I H- 1, 4 -benzodiazepin-2 -one; G whnRis 2 -phenylphenyl,
R
2 is Z is -CH 1 n is 1, and p is 1, then W, together with CH- and C does notE fo rm an 7 yr-H-lezb zpn6o H when R' is CH- 3 0C(O)CH 2 R' is -CH 3 Z is -CHC(0)-, is 1, and p is 1, then W, together with CH and C does not form an 2, 3-dihydro- Il-(t-butyIC(O)CH,+5)s.(2..pyridy I H 1 4 -benzod iazep in-.2 -one; I. when RI is 4 -ethoxyphenyl, 2 4 6 -rinethylphenyl, 4 -phenvlphenvl,
*CH
3
OC(O)CH-
2 4
-HOCH
2 -phenvl, 2,4, 6 -trifluorophenyl, 2 -trifluoromethy 1-4fluorophenyl, or CH 3 RI is -CH- 3 Z is is1anDis, then W, together with >CH and does not form a 2.3'-dihvdro-l-( 1 v,N diethylaminoCHCH 5 (2-pyridy I)-l H-i1, 4-bnoizpi- oe J. when
R
1 is 26dfurpey, R is -CH 3 1 Z is C(HCO, n is 1, and p is 1, then W, together with CH and C= X, does noti form a 2 3 2 -p 11y--1,4., benzodiazepin-2-one, K. when nis 1,then 12 Sw -C(H)p
C
II
X
does not equal cycloalkyl of from 3 to 8 carbon atoms optionally substituted with 1 to 3 alkyl groups; L. when n is 0 an W- together with is a nitrogen heterocycle having 5 through 7 ring atoms, one of which is nitrogen and the remainder of which are o carbon wherein X is oxo, then R is not alkyl substituted with -C(O)NHOH-) M. when n is 0 and -C(H)p together with forms a fused ring benzolactam in with the lactam nitrogen is substituted with an optionally substituted phenyl, biphenyl, phenylalkylene or biphenylalkylene substituent, and T is a bond then R' is not aminoalkylene or substituted aminoalkylene' N. W together with does not form a substituted or unsubstituted azetidinone.
12A Accordingly, in one of its method aspects, this invention is directed to a method for inhibiting -amyloid peptide release and/or its synthesis in a cell which method comprises administering to such a cell an amount of a compound or a mixture of compounds of formula I above effective in inhibiting the cellular release and/or synthesis of 3-amyloid peptide.
Because the in vivo generation of /-amyloid peptide is associated with the pathogenesis of AD" 9 the compounds of formula I can also be employed in conjunction with a pharmaceutical composition to prophylactically and/or therapeutically prevent and/or treat AD. Accordingly, in another of its method aspects, this invention is directed to a prophylactic method for preventing the onset of AD in a patient at risk for developing AD which method comprises Sadministering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I above.
o* WO 98/28268 PCT/US97/22986 13 In yet another of its method aspects, this invention is directed to a therapeutic method for treating a patient with AD in order to inhibit further deterioration in the condition of that patient which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I above.
In formula I above, when m is zero there is a covalent bond from
R
1 to NH), R 1 is preferably aryl (including substituted aryl) or heteroaryl (including substituted heteroaryl). In this embodiment, further preferred R' groups include phenyl, a substituted phenyl group of the formula: Rb' Rc Rb wherein Rc is selected from the group consisting of acyl, alkyl, alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, and wherein Rb and Rc are fused to form a heteroaryl or heterocyclic ring with the phenyl ring wherein the heteroaryl or heterocyclic ring contains from 3 to 8 atoms of which from 1 to 3 are heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur Rb and Rb' are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy, and thioalkoxy with the proviso that when RC is hydrogen, then Rb and Rb' are either both hydrogen or both substituents other than hydrogen, 2-naphthyl, WO 98t28268 PCTI/US97/22986 14-- 2-naphthyl substituted at the 4, 5, 6, 7 and/or 8 positions with 1 to substituents selected from the group consisting alkyl, alkoxy, halo, cyano, itro, trihalomethyl, thioalkoxy, aryl, and heteroaryl, heteroaryl, and substituted heteroaryl containing 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl, thioalkoxy, thioaryloxy provided that said substituents are not ortho to the heteroaryl attachment to the -NH group.
When m is zero, particularly preferred substituted phenyl R1 groups include mono-, di- and tn-substituted phenyl groups including phenyls such as 3,5-dichlorophenyl, 3,5-difluorophenyl, phenyl, etc.; 3,4-disubstituted phenyls such as 3,4-dichlorophenyl, 3,4difluorophenyl, 3-(trifluoromethyl)-4-chlorophenyl, 3-chloro-4-cyanophenyl, 3-chloro-4-iodophenyl, 3 ,4-methylenedioxyphenyl, etc.; 4-substituted phenyls such as 4-azidophenyl, 4-bromophenyl, 4-chlorophenyl, 4-cyanophenyl, 4-ethylphenyl, 4-fluorophenyl, 4-iodophenyl, 4-(phenylcarbonyl)phenyl, 1ethoxy)ethylphenyl, etc., 3,4,5-trisubsituted phenyls such as 3,4,5trifluorophenyl, 3,4, 5-trichlorophenyl, etc.
Specific R' groups for when m is zero include 3,4-dichiorophenyl, 4phenylfurazan-3-yl, and the like.
When m is zero, other preferred RI substituents include, by way of example, 2-naphthyl, quinolin-3-yl, 2-methylquinolin-6-yl, benzothiazol-6-yi, indolyl, phenyl, and the like.
When m is one, preferred RI groups include unsubstituted aryl groups such as phenyl, 1-naphthyl, 2-naphthyl, etc.; substituted aryl groups such as monosubstituted phenyls (preferably substituents at 3 or 5 positions); disubstituted phenyls (preferably substituents at 3 and 5 positions); and WO 98/28268 PCT/US97/22986 15 trisubstituted phenyls (preferably substituents at the 3,4,5 positions).
Preferably, the substituted phenyl groups do not include more than 3 substituents. Examples of substituted phenyls include, for instance, 2-chiorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl, 2trifluoromethyiphenyl, 4-fluorophenyl, 4-chiorophenyl, 4-bromophenyl, 4nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4ethoxyphenyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl, 4trifluoromethyiphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl, 3hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chiorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methyiphenyl, 3trifluoromethylphenyl, 2, 3-dichiorophenyl, 2, 3-difluorophenyl, 2,4dichiorophenyl, 2 ,5-dimethoxyphenyl, 3 ,4-dichlorophenyl, 3 ,4-difluorophenyl, 3 ,4-methylenedioxyphenyl, 3 ,4-dimnethoxyphenyl, 3, 5-difluorophenyl, dichiorophenyl, 3 ,5-di-(trifluoromethyl)phenyl, 3, 5-dimethoxyphenyl, 2,4dichlorophenyl, 2 ,4-difluorophenyl, 2, 6-difluorophenyl, 3,4 3,4, 5-trimethoxyphenyl, 3,4, 5-tri-(trifluoromethyl)phenyl, 2,4 ,6-trifluorophenyl, 2,4, 6-trimethyiphenyl, 2,4 ,6-tri-(trifluoromethyl)phenyl, 2,3 2,4, 5-trifluorophenyl, 2, 5-difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 4benzyloxyphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,3,4,5,6pentafluorophenyl, 2, 5-dimethylphenyl, 4-phenylphenyl, 2-fluoro-3trifluoromethyiphenyl, When m is one, other preferred R' groups include, by way of example, adamantyl, benzyl, 2-phenylethyl, 3-phenyl-n-propyl, 4-phenyl-n-butyl, methyl, ethyl, n-propyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-valeryl, n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopent-l1-enyl, cyclopent-2-enyl, cyclohex-l1-enyl, -CH,-cyclopropyl, -CH 2 -cyclobutyl, -CH,cyclohexyl, -C11-cyclopentyl, -CH,CH,-cyclopropyl, -CH,CH,-cyclobutyl, WO 98/28268 PTU9128 PCT/US97/22986 16--
-CH
2
CH
2 -CYClohexyl, -CH 2 CH,-cyclopentyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3-yl), chioropyridyls (including chloropyrid-3-yl), thien-2-yl, thien-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazolfuran-2-yl, benzofuran-2-yl, thionaphthen-2-yl, thionaphthen-3-yl, thionaphthen-4-yl, 2-chlorothiophen-5-yl, 6-methoxythionaphthen-2-yl, 3-phenyl- 1,2,4- 2-phenyloxazol-4-yl, indol-3-yl, 1 -phenyl-tetraol-5-yl, allyl, 2-(cyclohexyl)ethyl, (CH 3 2 CH =CHCHCH 2
CH(CH
3 4kC(O)CH 2 thien-2-ylmethyl, 2-(thien-2-yl)ethyl, 3-(thien-2-yl)-n-propyl, 2-(4-nitrophenyl)ethyl, 2-(4methoxyphenyl)ethyl, norboran-2-yl, (4-methoxyphenyl)methyl, (2methoxyphenyl)methyl, (3-methoxyphenyl)methyl, (3-hydroxyphenyl)methyl, (4-hydroxyphenyl)methyl, (4-methoxyphenyl)methyl, (4-methylphenyl)methyl, (4-fluorophenyl)methyl, (4-fluorophenoxy)methyl, (2 ,4-dichlorophenoxy)ethyl, (4-chlorophenyl)methyl, (2-chlorophenyl)methyl, (1 -phenyl)ethyl, (1 chlorophenyl)ethyl, (1 -trifluoromethyl)ethyl, (4-methoxyphenyl)ethyl,
CH
3
OC(O)CH
2 benzylthiomethyl, 5-(methoxycarbonyl)-n-pentyl, 3- (methoxycarbonyl)-n-propyl, indan-2-yl, (2-methylbenzofuiran-3-yl), methoxymethyl, CH 3 CH =CII-, CH 3
CH
2 CH (4-chlorophenyl)C(O)CH 2 (4-fluorophenyl)C(O)CH 2 (4-methoxyphenyl)C(O)CH 2 4-(fluorophenyl)- NHC(O)CH,-, 1 -phenyl-n-butyl, (0) 2
CHNHC(O)CH
2
CH
2
(CH
3 )2NC(O)CH,-, (4) 2
CHNHC(O)CHCH
2 methylcarbonylmethyl, (2,4dimethylphenyl)C(O)CH 2 4-methoxyphenyl-C(O)CH 2 phenyl-C(O)CH,-,
CH
3 ethenyl, methyithiomnethyl, (CH 3 3
CNIIC(O)CH
2 4fluorophenyl-C(O)CH 2 diphenylmethyl, phenoxymethyl, 3,4methylenedioxyphenyl-CH 2 benzo[b] thiophen-3-yl, (C11 3 3 COC(O)NHCH2-, trans-st yryl, H,NC(O)CH,CH 2 2-trifluoromethylphenyl-C(O)CH,,
OC(O)NH-CH(O)CH
2 mesityl, CH 3 CH( =NHOH)CH,-, 4-CH 3 -cj-
NHC(O)CH
2
CH
2
OC(O)CH(O)CH
2
(CH
3 )2CHC(O)NHCH(O)-,
CH
3
CH
2
OCH
2
CH
3
OC(O)CH(CH
3
)(CH
2 3 2,2 ,2-trifluoroethyl, 1- (trifluoromethyl)ethyl, 2-CH 3 -benzofuran-3-yl, 2-(2 ,4-dichlorophenoxy)ethyl, OSO,CH,-, 3-cyclohexyl-n-propyl, CF 3 CH,CH,CH2- and N-pyrrolidinyl.
WO 98/28268 PCT/US97/22986 17 Still other preferred R' groups include those set forth in the Tables below.
When n is one or two, each R 2 is preferably (and independently for n 2) selected from the group consisting of alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic.
Particularly preferred R' substituents include, by way of example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,
-CH,CH(CH
2
CH
3 2 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cy clohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl,
-CH
2 -cyclopropyl, -CH 2 -cyclohexyl, -CH 2
CH
2 -cyclopropyl,
-CH
2
CH
2 -cyclohexyl, -CH 2 -indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH 3 2
NCH
2
CH
2
CH
2 O-benzyl, p-(CH 3 3
COC(O)CH
2 O-benzyl, p-(HOOCCH 2 O)-benzyl, 2-aminopyrid-6-yl, p- (N-morpholino-CH 2
CH
2 O)-benzyl, -CH 2
CH
2 C(O)N1 2
-CH
2 -imidazol-4-yl,
-CH
2 -(3-tetrahydrofuiranyl), -CH,-thiophen-2-yl, -C11 2 1-methyl)cyclopropyl, -CH,-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, -CH,-C(O)O-t-butyl, -CH--
C(CH
3 3
-CH
2
CH(CH
2
CH
3 2 -2-methylcyclopentyl, -cyclohex-2-enyl,
-CH[CH(CH
3 )21COOCH 3
-CH
2
CH
2
N(CH
3 2
-CH
2
C(CH
3
=CH
2 -CfI 2 CH =CHCH 3 (cis and trans), -CH 2 OH, -CH(OH)CH 3 -CH(O-t-butyl)CH 3
-CH.,OCH
3
-(CH
2 4 NH-Boc, 4
NH
2
-CH
2 -pyridyl 2-pyridyl, 3pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), -CH,naphthyl 1-naphthyl and 2-naphthyl), -CH 2 -(N-morpholino), p-(Nmorpholino-CH 2
CH
2 O)-benzyl, benzo[blthiophen-2-yl, chlorobenzo[blthiophen-2-yl, 4,5 ,6,7-tetrahydrobenzo[blthiophen-2-yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[bjthiophen-5-yl, 6methoxynaphth-2-yl, -CH,CH,SCH 3 thien-2-yl, thien-3-yl, and the like.
WO 98/28268 PCTIUS97t22986 18 Compounds of this invention include, by way of example, 1 -(3,5-iloohnlctl -laiy)aioiezsbrn 1 ,5-difluorophenylacetyl)-L-alaninyl)-amino-2(S)inda 1 oI 1 ,5-difluorophenylacetyl)-L-alaninyl)-amino2-(R)-indanoI 1 S-difluorophenylacetyl)-L-alaninyl)-amino-2.indanoI 2-(N ,5-difluorophenylacetyl)-L-alaninyl)-amino-. 1-cyclohexanol 1 S-difluorophenylacetyl)-L-alaninyl).amino. 1,2,3,4tetrahydro-2-naphthol 1 '-(3,5-iloohnlctl -lnny)aioezfccoetn2 ol [N ,5-difluorophenylacetyl)-L-alaninyllamino-5 ,7-dihydro-6Hdibenzo[a,clcyclohepten-6-ol 1 ,5-difluorophenylacetyl)-L-alaninyl)-aminoindan2one 2-(N '-(phenylacetyl)-L-alaninyl)aminocyclohexan- 1 -one ,5-difluorophenylacetyl)-L-alaninyllamino- 7-dihydro-6Hdibenzo[a, c]cyclohepten-6-one 3-(N S-difluorophenylacetyl)-L-alaninyl)-amino--..butyrolactone 3-(N 4 -dichlorophenyl)-L-alaniny)amino--y-butyrolactone 4-(N '-(cyclopentylacetyl)-L-alaninyl)amino- 1, 1 -dimethyl-3isochromanone 4-(N 5-difluorophenylacetyl)-L-alaninyl)amino- 1, 1-dimethyl-3isochromanone 3-(N S-difluorophenylacetyl)-L-alaninyl)amino-y-butyrolactam 3-(N ,5-difluorophenylacetyl)-L-alaninyl)amino-6-valerolactarn 1 -benzyl-3-(S)-(N ,5-difluorophenylacetyl)-L-alaninyly..amino-6valerolactamn 3-N .5-difluorophenylacetyl)-L-alaninyl)amino4methyl1E-caprolactam WO 98/28268 WO 9828268PCT1US97t22986 19-- 5-difluorophenylacetyl)-L-alaninyl)amino- 1,2,3,4tetrahydroquinolin-2-one 1 -benzyl-3-(N 5-difluorophenylacetyl)-L-alaninyl)amino- 1,2,3,4tetrahydroquinolin-2-one 4-(N ,5-difluorophenylacetyl)-L-alaninyl)amino- 1,2,3,4tetrahydroisoquinolin-3-one ,5-difluorophenylacetyl)-L-alaninyl)amino-2-benzyl- 1,2,3,4tetrahydroisoquinolin-3-one ,5-difluorophenylacetyl)-L-alaninyl)amino- 1 -methyl-i ,2 ,3,4tetrahydroisoquinolin-3-one 4-(N ,5-difluorophenylacetyl)-L-alaninyl)anino- 1 -phenyl- 1,2,3,4tetrahydroisoquinolin-3-one 4-(N ,5-difluorophenylacetyl)-L-alaninyl)amino-6-fluoro- 1,2,3,4tetrahydroisoquinolin-3-one 4-(N 5-difluorophenylacetyl)-L-alaninyl)amino-7-fluoro- 1,2,3,4tetrahydroisoquinolin-3-one 4-(N ,5-difluorophenylacetyl)-L-alaninyl)amino-2-phenethyl- 1,2,3,4tetrahydroisoquinolin-3 -one 4-(N 5-difluorophenylacetyl)-L-alaninyl)amino-2-methyl- 1,2,3,4tetrahydroisoquinolin-3-one ,5-difluorophenylacetyl)-L-alaninyl)amino-6-phenyl- 1,2,3,4tetrahydroisoquinolin-3 -one 4-(N ,5-difluorophenylacetyl)-L-alaninyl)amino-7-phenyl- 1,2,3,4tetrahydroisoquinolin-3-one (N ,5-difluorophenylacetyl)-L-alaninyl)-(9-aminofluroren- 1 -yl)glycine b-lactam 3-(N '-(phenylacetyl)-L-alaninyl)anino-c--caprolactam 5-difluorophenylacetyl)-L-alaninyl)amino-l1-benzyl-Ecaprolactamn WO 98/28268 PCTIUS97/22986 20 ,5-difluorophenylacetyl)-L-alaninyl)amino- 1 -(2-methoxyethyl)- E-caprolactam 5-difluorophenylacetyl)-L-alaninyl)amino-l1-ethyl-Ecaprolactam 3-N 3-N 3-N ,5-difluorophenylacetyl)-L-alaniny-amino)-7-benzylcaprolactam 5-difluorophenylacetyl)-L-alaninyl)amino-l1-benzyl-4 .7methano-E-caprolactam 3()('-(cyclopentylacetyl)-L-alaninyl)amino-l1-benzyl-c--caprolactam '-(cyclopentylacetyl)-L-phenylglycinyl)amino- 1-benzyl-ecaprolactam 5-difluorophenylacetyl)-L-alaninyl)amino-l1-(2-phenethyl)-Ecaprolactam '-(cyclopentylacetyl)-L-phenylglycinyl)amino-l1-(2-phenethyl)-ecaprolactam 3-(N ,4-dichlorophenyl)-D ,L-alaninyl)amino-e-caprolactam '-(cyclopropylacetyl)-L-phenylglycinyl)amino- 1 -methyl-Ecaprolactam 3-(N '-(3,5-difluorophenylacetyl)-L-alaninyl)amino-8-octanelactam 4-(N ,5-difluorophenylacetyl)-L-alaninyl)amino-7-benzyl- 1,2,3,4tetrahydroisoquinolin-3-one 4-(N 5-difluorophenylacetyl)-L-alaninyl)amino-l1-benzyl- 1,2,3,4tetrahydroisoquinolin-3-one 4-(N ,5-difluorophenylacetyl)-L-alaninyl)amino-2-methyl-l1-phenyl- 1,2,3 ,4-tetrahydroisoquinolin-3-one 4-(N ,5-difluorophenylacetyl)-L-alaninyl)amino- 1 -(pyrid-2-yI)- 1,2,3,4tetrahydroisoquinolin-3-one WO 98/28268 PCTIUS97/22986 4-(N ,5-difluorophenylacetyl)-L-alaninyl)amino- 1 -(pyrid-3-yI)- 1,2,3,4tetrahydroisoquinolin-3-one 4-(N 5-difluorophenylacetyl)-L-alaninyl)amino- 1 -(pyrid-4-yl)- 1,2,3,4tetrahydroisoquinolin-3-one 3 5-difluorophenylacetyl)-L-alaninylI -amino-i1 -methyl-2indolinone 3 5-difluorophenylacetyl)-L-alaninyl]arnino- 1 -methyl-4-phenyl- 3 ,4-trans-dihydrocarbostyril 3-[N ,5-difluorophenylacetyl)-L-alaninyl] amino- I -methyl-4-phenyl- 3 ,4-cis-dihydrocarbostyril 3-N-35-difluorophenylacetyl)-L-alaninyl] amino-4-phenyl-3 ,4-transdihydrocarbostyril 1 5-difluorophenylacetyl)-L-alaninyl)amino-3-methyl- 1,3,4,5tetrahydro-2H-3-benzazepin-2-one 1 ,5-difluorophenylacetyl)-L-alaninyl)amino-3-ethyl-4' -fluoro- 1,3 ,4,5-tetrahydro-211-3-benzazepin-2-one 3-(3 ,5-difluorophenylacetyl)amino- 1 -ethyl-S ,5-dimethyl- 1, 3,4,5tetrahydro-2H- 1 -benzazepin-2-one 3-(N ,5-difluorophenylacetyl)-L-alaninyl)amino- 1, 3,4, 2H- 1-benzazepin-2-one 3-(N 5-difluorophenylacetyl)-L-alaninyl)amino-l1-benzyl- 1,3,4,5tetrahydro-2H-3-benzazepin-2-one 3-(N '-(cyclopentylacetyl)amino- 1 -ethyl-S. 5-dimethyl- 1,3,4, 2H- 1-benzazepin-2-one ,5-difluorophenylacetyl)-L-alaninyl)amino- 1-methyl-i, 3,4,5tetrahydro-2H- 1 -benzazepin-2-one 3-(N ,5-difluorophenylacetylI)-L-alaninyl)amino- 1, 5-dimethyl- 1, 3,4,5 tetrahydro-2H- 1 -benzazepin-2-one 3-(3 ,5-difluorophenylacetyl)amino- 1, 5-dimethyl- 1, 3,4 ,5-tetrahydro-211- 1 benzazepin-2-one -difluor-ophenylacetyl)-L-alaninyl)amino- 1 1, 3,4,5-tetrahydro-2H- 1-benzazepin-2-one WO 98/28268 WO 9828268PCT/US97I22986 22 5-difluorophenylacetyl)-L-alaninyl)amino-l1-ethyl-5-oxa- 1, 3,4, S-tetrahydro-2H- 1 -benzazepin-2-one ,5-difluorophenylacetyl)-L-alaninyl)amino-l1-methyl-5-thia- 1, 3,4, 5-tetrahydro-2H- 1 -benzazepin-2-one 5-difluorophenylacetyl)-L-alaninyl}-amino-3 ,3-dimethyl-5 .7dihydro-6H-benz[b~azepin-6.-one S-{N S-difluorophenylacetyl)-L-alaninyl~amino-3 ,3 ,7-trimethyl-5 .7dihydro-6H-benzblazepin-6-one ,5-difluoromandelyl] -L-alaninyllamino-3 ,3 ,7-trimethyl-5 .7dihydro-6H-benz[blazepin-6-one 1 ,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl- 1,3,4,5tetrahydro-2H-3-benzazepin-2-one S-difluorophenylacetyl)-L-alaninyl)amino- 1-ethyl-S,S -dimethyl- 1, 3,4,5-tetrahydro-2H- 1-benzazepin-2-one ,5-difluorophenylacetyl)-L-alaninyl]amino-7-methyl- 7dihydro-6H-dibenz[b, dlazepin-6-one and -difluorophenyl-o!-hydroxyacetyl)-L- ,7-dihydro-6H-dibenz[b,djazepin-6-one 5-difluorophenyl-a-ketoacetyl)-L-alaninyl] amino-7-methyl- S ,7-dihydro-6H-dibenz[b,dlazepin-6-one S-difluorophenylacetyl)-L-valinyllamino-7-methyl-S ,7dihydro-6H-dibenzllb,d]azepin-6-one ,5-difluorophenylacetyl)-L-tert-leucinyl]amino-7-methyl-5 ,7dihydro-6H-dibenz[b,dlazepin-6-one ,5-difluorophenyl-a-hydroxyacetyl)-L-valinyl]amino-7methyl-S ,7-dihydro-6H-dibenz[b,d]azepin-6-one leucinyl]amino-7-methyl- 7-dihydro-6H-dibenz[b,dlazepin-6-one 5-difluorophenylacetyl)-L-alaninyllamino-7-(methoxyacetyl)- ,7-dihydro-6H-dibenz[b,d]azepin-6-one S-[N 5-difluorophenylacetyl)-L-alaninyl] amino-7-(methylcarboxylate)- S ,7-dihydro-6H-dibenz[b,dlazepin-6-one WO 98/28268 PCTIUS97/22986 23 ,5-difluorophenylacetyl)-L-alaninyl]amino-7-(3 ,3-dimethyl-2- ,7-dihydro-6H-dibenz[b,djazepin-6-one ,5-difluorophenylacetyl)-L-alaninyl] amino-7-(morpholinylacetyl)- 5 ,7-dihydro-6H-dibenz[b,d]azepin-6-one +)-2-Hydroxy-3-methylbutyryl)-L-alaninyl)amino-7methyl-S ,7-dihydro-6H-dibenz[b ,dlazepin-6-one -cyclopentyl-ca-hydroxyacetyl)-L-valinyl]amino-7-methyl-s ,7dihydro-6H-dibenz[b,djazepin-6-one and ,3-dimethyl-2-hydroxybutyryl)-L-alaninyl)amino- 7-methyl-S ,7-dihydro-6H-dibenz[b,d]azepin-6-one '-ccoetlc-yrxyctl--etluinlaio7mty ,7dihydro-6H-dibenz[b ,dlazepin-6-one '-cyclopentyl-ci-hydroxyacetyl)-L-alaniny1]amino-7-methyl-s ,7dihydro-6H-dibenz[b,dlazepin-6-one ,5-difluorophenylacetyl)-L-alaninyl] amino-S ,7-dihydro-6H ,7Hdibenz[b,djazepin-6-one 5- [N 5-difluorophenylacetyl)-L-alaninyl] amino-7-(2-methylpropyl)- ,7-dihydro-6H-dibenz[b,djazepin-6-one -(2-hydroxy-3-methylbutyryl)-L-valinyllamino-7-methyl-s ,7dihydro-6H-dibenz[b,d]azepin-6-one and R)-2-hydroxy-3 ,3-dimethylbutyryl)-L-valinyl]amino-7methyl-S ,7-dihydro-6H-dibenz[b ,dlazepin-6-one '-(4-phenyl-furazan-3-yl)alaninyl} -amino-7-methyl-5 ,7-dihydro-6Hdibenz[b ,d]azepin-6-one 5-difluorophenylacetyl)-L-alaninyl~amino-7-methyl- 1,2,3,4,5,7hexahydro-6H-dicyclohexyl[b,djazepin-6-one 5- {N ,5 -difluorophenylacetyl)-L-alaninyl }amino-7-phenbutyl-5 ,7dihydro-6H-dibenz[b azepin-6-one S-difluorophenylacety1)-L-alaninylamino-7-cyclopropymethyl- ,7-dihydro-6H-dibenzb,dlazepin-6-one '-(3.5-difluorophenylacetyl)-L-alaninyl} amino-7-(2' ,7-dihydro-H-dibenz[b azepin-6-one WO 98/28268 PCT/US97/22986 24-- ,5-difluorophenylacetyl)-L-alaninyl }amino-7-cyclohexyl-5 ,7dihydro-.6H-dibenz[b ,d]azepin-6-one ,5-difluoromandelyll -L-alaninyl~amino-9-fluoro-7-methyl- 5 ,7-dihydro-6H-dibenz[b,d]azepin-6-one ,5-difluoromandelyl] -L-alaninyl} -amino-i 3-fluoro-7-methyl- S ,7-dihydro-6H-dibenzjlb,d]azepin-6-one 5-{f ,5 -difluoromandelyl] -L-alaninyl) amino- 1 0-fluoro-7-methyl- ,7-dihydro-6H-dibenz[b,d]azepin-6-one {N ,5-difluoromandelyl] -L-alaninyl~amino-7-cyclopropylmethyl- 7-dihydro-6H-dibenz[b,d]azepin-6-one ,5-difluoromandelyl] -L-alaninyl~aniino-7-phenbutyl-5 .7dihydro-6H-dibenzllb,d]azepin-6-one ,5-difluoromandelyl] -L-valinyl~amino-7-cyclopropylmethyl- 5, 7-dihydro-6H-dibenz[b,d]azepin-6-one ,5-difluoromandelyi] -L-valinyl~amino-7-phenbutyl-5 ,7dihydro-6H-dibenz[b,djazepin-6-one 5- {N ,5-difluoromandelyll-L-valinyl~amino-7-hexyl-5 ,7-dihydro- 6H-dibenz[b ,djazepin-6-one N '-[(S)-3.,5-difluoromandelyl]-L-valinyl amino-i1 0-fluoro-7-methyl- 7-dihydro-6H-dibenz[b,d]azepin-6-one ,5-difluoromandelyl] -L-valinyl1)amino- 1 3-fluoro-7-methyl- 7-dihydro-6H-dibenz[b,d]azepin-6-one ,5-difluoromandelyl]-L-valinyl} amino-9-fluoro-7-methyl-5 ,7dihydro-6H-dibenz[b,dJ azepin-6-one 3-(N ,4-methylenedioxyphenylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1methyl-5-phenyl-l1i,4-benzodiazepin-2-one 3-(N '-(2-methoxyphenoxyacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1-methyl- 5-phenyl-l1H-i ,4-benzodiazepin-2-one -(4-isopropylphenoxyacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1methyl-5-phenyl-l1H-i ,4-benzodiazepin-2-one 3-(N '-(ethoxyacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 1H- 1 ,4-benzodiazepin-2-one WO 98/28268 WO 9828268PCTIUS97/22986 25 3-(N '-(4-phenoxyphenylacetyl)-L-alaninyl)amino-2 ,3-dihydro- I phenyl-l1H-i ,4-benzodiazepin-2-one 3-(N '-(4-ethoxyphenylacetyl)-L-alaninyl)amino-2 ,3-dihydro-l1-methyl-5phenyl-1IH- 1 ,4-benzodiazepin-2-one ,5-dimethoxyphenylacetyl)-L-alaninyl)aznino-2 ,3-dihydro- 1- 1H-i ,4-benzodiazepin-2-one ,5-difluorobenzoyl)-L-alaninyl)amino-2 ,3-dihydro- 1 phenyl-l1H-i ,4-benzodiazepin-2-one 3-(N '-(o-tolylacetyl)-L-alaninyl)amino-2 ,3-dihydro-l1-methyl-5-phenyl- 1 H-i ,4-benzodiazepin-2-one 3-(N ,3-diphenylpropionyl)-L-alaninyl)amino-2 ,3-dihydro- 1 phenyl- 1H-i ,4-benzodiazepin-2-one -(3-phenoxypropionyl)-L-alaninyl)amino-2 ,3-dihydro- 1 phenyl-1H- 1,4-benzodiazepin-2-one -(indole-3-acetyl)-L-alaninyl)amino-2, 3-dihydro-l1-methyl-5-phenyl- LH- 1,4-benzodiazepin-2-one -(4-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1lH- 1,4-benzodiazepin-2-one 3-(N '-((4-methylphenoxy)acetyl)-L-alaninyl)amino-2 ,3-dihydro- 1-methyllH- 1,4-benzodiazepin-2-one 3-(N '-(4-(hydroxymethyl)phenoxyacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 -methyl-5-phenyl-l1H-i ,4-benzodiazepin-2-one 3-(N '-(2-phenoxyphenylacetyl)-L-alaninyl)amino-2 ,3-dihydro-l1-methyl-5phenyl- lH- 1,4-benzodiazepin-2-one -(3-phenoxyphenylacetylt)-L-alaninyl)amrino-2, 3-dihydro-l1-methyl-5phenyl- 1H- 1,4-benzodiazepin-2-one 3-(N ,4-dichlorophenoxyacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1- 1H- 1,4-benzodiazepin-2-one 3-(N '-(4-fluorophenoxyacetyl)-L-alaninyl)amino-2 3-dihydro-l1-methyl-5phenyl- 1H-i ,4-benzodiazepin-2-one 3 -(methylthio)acetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 phenyl- 1H- 1,4-benzodiazepin-2-one WO 98/28268 WO 9828268PCT1US97/22986 26-- 3-(N '-(methoxyacetyl)-L-alaninyl)amino-2 ,3-dihydro-l1-methyl-5-phenyl- 1H- 1 ,4-benzodiazepin-2-one '-(phenoxyacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 phenyl-lH- 1 ,4-benzodiazepin-2-one '-(phenylacetyl)-L-alaninyl)amino-2, 3-dihydro-l1-methyl-5phenyl- 1H-i ,4-benzodiazepin-2-one '-(2-phenoxybutyryl)-L-alaninyl)amino-2 ,3-dihydro- 1 phenyl- 1H- 1 ,4-benzodiazepin-2-one -(3-methoxyphenoxyacetyl)-L-alaninyl)amino-2 ,3-dihydro- I1methyl-5-phenyl-l1H-i ,4-benzodiazepin-2-one '-(4-(trifluoromethyl)phenylacetyl)glycinyl)-L-alaninyl)aniino- 2, 3-dihydro-l1-methyl-5-phenyl-l1H-i ,4-benzodiazepin-2-one '-(4-butoxyphenylacetyl)-L-alaninyl)amino-2 ,3-dihydro-l1-methyl- 5-phenyl- 1H-i ,4-benzodiazepin-2-one -(3-(2-methoxyphenyl)propionyl)-L-alaninyl)amino-2 ,3-dihydro- 1 -methyl-5-phenyl- 1 H-i ,4-benzodiazepin-2-one '-(4-fluorophenylacetyl)-L-alaninyl)aniino-2 ,3-dihydro- 1-methyl- 1H-1 ,4-benzodiazepin-2-one '-(isopropoxylacetyl)-L-alaninyl)amino-2, 3 -dihydro- 1 phenyl- 1H- 1 ,4-benzodiazepin-2-one -phenyl- 1H-tetrazole-5-acetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 -methyl-5-phenyl-l1H-i ,4-benzodiazepin-2-one ,4-methylenedioxyphenyl)propionyl)-L-alaninyl)amino- 2, 3-dihydro- 1 -methyl-5-phenyl- 1 H-i ,4-benzodiazepin-2-one -(3-cyclopentylpropionyl)-L-alaninyl)amino-2 ,3-dihydro- 1 1H-i ,4-benzodiazepin-2-one '-(2-cyclopentene- 1 -acetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 1H-i ,4-benzodiazepin-2-one -(2-chloro-6-fluorophenylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 -methyl-5-phenyl-L1H- 1 ,4-benzodiazepin-2-one '-(cyclohexylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 phenyl-l1H-i ,4-benzodiazepin-2-one WO 98/28268 WO 9828268PCT[US97/22986 27 ,5-difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro- 1- 1H-1 ,4-benzodiazepin-2-one -(pentafluorophenoxyacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 methyl-5-phenyl- 1H- 1 ,4-benzodiazepin-2-one ,5-dimethylphenoxyacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1- 1H- 1,4-benzodiazepin-2-one '-(4-chlorophenylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1-methyl- 5-phenyl-1H- 1,4-benzodiazepin-2-one (S)-3-(N'-(3-chlorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro- 1- 1H- 1,4-benzodiazepin-2-one '-(benzo[b] thiophene-3-acetyl)-L-alaninyl)axnino-2 ,3-dihydro- 1 methyl-5-phenyl-l1H-i ,4-benzodiazepin-2-one -(benzoylformnyl)-L-alaninyl)amino-2 ,3-dihydro- 1 phenyl-1H- 1,4-benzodiazepin-2-one ,5-dimethoxyphenylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 1H- 1,4-benzodiazepin-2-one -(2,5-dimethylphenylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1methyl-5-phenyl-1H- 1,4-benzodiazepin-2-one 6-difluorophenylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 LH- 1,4-benzodiazepin-2-one ,4-difluorophenylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1- 1H- 1,4-benzodiazepin-2-one (S)-3-(N'-(mesitylacetyl)-L-alaninyl)amino-2,3-dihydro- I phenyl-1H- 1,4-benzodiazepin-2-one (S)-3-(N'-(4-biphenylacetyl)-L-alaninyl)amino-2,3-dihydro-l1-methyl-5phenyl- 1H- 1 ,4-benzodiazepin-2-one difluorophenylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1- 1H- 1,4-benzodiazepin-2-one '-(trans-styrylacetyl)-L-alaninyl)amino-2 ,3-dihydro-l1-methyl-5phenyl- 1H- 1 ,4-benzodiazepin-2-one '-(3-benzoylpropionyl)-L-alaninyl)amino-2, 3-dihydro-l1-methyl-5phenyl- 1H- 1,4-benzodiazepin-2-one WO 98/28268 PCT1US97/22986 28 '-(trans-3-hexenoyl)-L-alaninyl)amino-2 ,3-dihydro-l1-methyl-5phenyl-l1H-i ,4-benzodiazepin-2-one '-(heptanoyl)-L-alaninyl)amino-2 ,3-dihydro-l1-methyl-5-phenyl- 1H-1 ,4-benzodiazepin-2-one '-(3-(4-methylphenyl)propionyl)-L-alaninyl)amino-2 ,3-dihydro- 1 1H-i ,4-benzodiazepin-2-one '-(3-(4-chlorophenyl)propionyl)-L-alaninyl)amino-2 ,3-dihydro- 1- 1H-i ,4-benzodiazepin-2-one '-(3-phenylbutyryl)-L-alaninyl)amino-2 ,3-dihydro- 1 phenyl- 1H-i ,4-benzodiazepin-2-one '-(4-(4-methoxyphenyl)butyryl)-L-alaninyl)arnino-2 ,3-dihydro- 1 1H-i ,4-benzodiazepin-2-one '-(3-methoxycarbonylpropionyl)-L-alaninyl)amino-2 ,3-dihydro- 1 methyl-5-phenyl- 1 H-i ,4-benzodiazepin-2-one '-(4-phenylbutyryl)-L-alaninyl)amino-2 ,3-dihydro-l1-methyl-5phenyl- 1 H-i ,4-benzodiazepin-2-one '-(3-(benzylthio)propionyl)-L-alaninyl)amino-2 ,3-dihydro- 1- 1H-i, 4-benzodiazepin-2-one '-(3-methylpentanoyl)-L-alaninyl)amino-2 ,3-dihydro-l1-methyl-5phenyl-l1H-i ,4-benzodiazepin-2-one -(6-methoxycarbonylheptanoyl)-L-alaninyl)amino-2 ,3-dihydro- 1methyl-5-phenyl-l1H-i ,4-benzodiazepin-2-one (S)-3-(N'-(2-indanylacetyl)-L-alaninyl)amino-2 ,3-dihydro- I phenyl-iH-i ,4-benzodiazepin-2-one '-(4-methoxyphenylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 iH-i ,4-benzodiazepin-2-one 2 -chlorophenoxyacetyl)-L-alaninyl)ainino-2 ,3-dihydro- I1- 1H-i ,4-benzodiazepin-2-one -(2-thiopheneacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 phenyl- 1 H-i ,4-benzodiazepin-2-one 3 -(trifluoromethyl)phenylacetyl)-L-alaninyl)amino-2 ,3- 1H-i ,4-benzodiazepin-2-one WO 98/28268 PTU9128 PCTIUS97/22986 29 -(4-tolylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 phenyl- 11-1 ,4-benzodiazepin-2-one ,6-difluoromandelyl)-L-alaninyl)amino-2, 3-dihydro- 1 -methyl- 5-phenyl-1H-1 ,4-benzodiazepin-2-one '-(-(4-methoxyphenyl)propionyl)-L-alaninyl)amino-2.3-dihydro- 1 -methyl-5-phenyl-l1H-i ,4-benzodiazepin-2-one ,5-difluorophenylacetyl)-L-alaninyl)amino-2, 3-dihydro- 1- 1H- 1,4-benzodiazepin-2-one '-(m-tolylacetyl)-L-alaninyl)amino-2 ,3-dihydro-l1-methyl-5phenyl-l1H-i ,4-benzodiazepin-2-one '-(3-fluorophenylacetyl)-L-alaninyl)amino-2, 3-dihydro- 1i-methyllH- 1,4-benzodiazepin-2-one (S)-3-(N'-(4-chlorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro- 1 methyl-5-phenyl- 1H- 1,4-benzodiazepin-2-one -(2-naphthylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 phenyl-l11-1 ,4-benzodiazepin-2-one '-(3-chlorophenylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1-methyl- 5-phenyl-1H-1 ,4-benzodiazepin-2-one -(3-methylphenoxyacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 1H-i, 4-benzodiazepin-2-one ,4-methylenedioxyphenylacetyl)-L-alaninyl)amino-2, 3- 1H-i ,4-benzodiazepin-2-one -(2-methoxyphenoxyacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1methyl-5-phenyl- 1 H- 1,4-benzodiazepin-2-one '-(4-isopropylphenoxyacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1methyl-5-phenyl-l1H-i ,4-benzodiazepin-2-one '-(4-phenoxyphenylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 1H-i ,4-benzodiazepin-2-one '-(phenylmercaptoacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 methyl-5-phenyl-l1H-i ,4-benzodiazepin-2-one '-(4-ethoxyphenylacetyl)-L-alaninyl)amino-2, 3-dihydro- 1-methyl- 1 H- 1 ,4-benzodiazepin-2-one WO 98t28268 WO 9828268PCT1US97/22986 30 5-dimethoxyphenylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 1 H-i ,4-benzodiazepin-2-one -(o-tolylacetyl)-L-alaninyl)amino-2 ,3-dihydro- phenyl-1H-1 ,4-benzodiazepin-2-one 3-diphenylpropionyl)-L-alaninyl)amino-2 ,3-dihydro- 1- 1H- 1,4-benzodiazepin-2-one '-(3-phenoxypropionyl)-L-alaninyl)amino-2 ,3-dihydro- 1-methyl- 5-phenyl-1IH- 1 ,4-benzodiazepin-2-one '-(indole-3-acetyl)-L-alaninyl)amino-2 ,3-dihydro-l1-methyl-5phenyl-l1H-i ,4-benzodiazepin-2-one '-(4-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino-2 ,3dihydro-l1-methyl-5-phenyl-l1H-i .4-benzodiazepin-2-one ,5-bis(trifluoromethyl)phenylacetyl)-L-alaninyl)amino-2 ,3dihydro- 1-methyl-5-phenyl-l1H-i ,4-benzodiazepin-2-one -(2-phenoxyphenylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1- 1H- 1,4-benzodiazepin-2-one -(3-phenoxyphenylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1- 1H- 1,4-benzodiazepin-2-one '-(4-fluorophenoxyacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1methyl-5-phenyl-1H- 1,4-benzodiazepin-2-one ,4-dichlorophenylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1- 1,4-benzodiazepin-2-one '-((methylthio)acetyl)-L-alaninyl)amino-2 ,3-dihydro-l1-methyl-5phenyl-1H- 1,4-benzodiazepin-2-one '-(4-fluoromandelyl)-L-alaninyl)amino-2 ,3-dihydro-l1-methyl-5phenyl- 1H- 1.4-benzodiazepin-2-one '-(4-thionaphthenacetyl)-L-alaninyl)amino-2 ,3-dihydro-l1-methyl- 1H- 1 4-benzodiazepin-2-one '-(methoxyacetyl)-L-alaninyl)amino-2 ,3-dihydro- phenyl-1H- 1,4-benzodiazepin-2-one '-(ethoxyacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 phenyl- 1H-i ,4-benzodiazepin-2-one WO 98/28268 PCTIUS97/22986 31 '-(3-indolepropionyl)-L-alaninyl)amino-2 ,3-dihydro- 1 phenyl- 1 H-i ,4-benzodiazepin-2-one '-(3-(2-chlorophenyl)propionyl)-L-alaninyl)amino-2 ,3-dihydro- 1 methyl-5-phenyl-1H-1 ,4-benzodiazepin-2-one.
'-(butyryl)-L-alaninyl)amino-2, 3-dihydro-l1-methyl-5-phenyl- IH- 1 ,4-benzodiazepin-2-one -(hexanoyl)-L-alaninyl)amino-2 ,3-dihydro- 1 iB- 1 ,4-benzodiazepin-2-one '-(5-phenylpentanoyl)-L-alaninyl)amino-2 ,3-dihydro- 1 phenyl- 1H-i ,4-benzodiazepin-2-one '-(4-(2-thienyl)butyryl)-L-alaninyl)amino-2 ,3-dihydro-l1-methyl- 5-phenyl-l1H-i ,4-berizodiazepin-2-one '-(4-nitrophenoxyacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 -methyl- 5-phenyl-l1H-i ,4-benzodiazepin-2-one '-(3-(3-methoxyphenyl)propionyl)-L-alaninyl)amino-2 ,3-dihydro- 1 -methyl-5-phenyl- 1H- 1,4-benzodiazepin-2-one '-(5-methylhexanoyl)-L-alaninyl)amino-2 ,3-dihydro- 1 phenyl- IH- 1 ,4-benzodiazepin-2-one '-(hydrocinnamyl)-L-alaninyl)amino-2 ,3-dihydro-l1-methyl-5phenyl- 1H- 1,4-benzodiazepin-2-one '-(octanoyl)-L-alaninyl)amino-2 ,3-dihydro- 1 H-i ,4-benzodiazepin-2-one '-(3-(3-hydroxyphenyl)propionyl)-L-alaninyl)amino-2 ,3-dihydro- 1-methyl-5-phenyl-1H-1 ,4-benzodiazepin-2-one -(3-(4-hydroxyphenyl)propionyl)-L-alaninyl)amino-2 ,3-dihydro- 1 -methyl-5-phenyl- LH- 1,4-benzodiazepin-2-one ,4,5-trifluorophenylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 methyl-5-phenyl-l1H-i ,4-benzodiazepin-2-one '-(5-hydantoinacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 phenyl- 1 H-i ,4-benzodiazepin-2-one '-(cyclopentylacetyl)-L-alaninyl)amino-2 ,3-dihydro- I phenyl- LH- 1 ,4-benzodiazepin-2-one WO 98/28268 PCTUS97/22986 32 '-(3-(trifluoromethy)butyry)-L-alaninyl)amino-2 ,3-dihydro- 1- 1 H-i ,4-benzodiazepin-2-one -(2-methyl-3-Benzofuranacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 methyl-5-phenyl- 1H- 1 ,4-benzodiazepin-2-one '-(propionyl)-L-alaninyl)amino-2, 3-dihydro- 1 111-1 ,4-benzodiazepin-2-one '-(cyclopropylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 phenyl- 1H- 1 ,4-benzodiazepin-2-one -(3-methoxypropionyl)-L-alaninyl)amino-2 ,3-dihydro- I1-methyl- 5-phenyl-l1H-i ,4-benzodiazepin-2-one '-(5-(thienyl)pentanoyl)-L-alaninyl)amino-2 ,3-dihydro- 1-methyl- 1H- 1,4-benzodiazepin-2-one (S)-3-(N'-(3-(4-fluorophenyl)propionyl)-L-alaninyl)amino-2,3-dihydro- 1methyl-5-phenyl- 1H- 1,4-benzodiazepin-2-one -(3-(4-fluorophenoxy)propionyl)-L-alaninyl)amino-2 ,3-dihydro- 1 -methyl-5-phenyl- 1H- 1,4-benzodiazepin-2-one -(2-norbornaneacetyl)-L-alaninyl)amino-2 ,3-dihydro-l1-methyl-5phenyl-1H- 1,4-benzodiazepin-2-one 3-difluoromandelyl)-L-alaninyl)amino-2 ,3-dihydro- 1-methyl- 1 H-i ,4-benzodiazepin-2-one '-(3-pentenoyl)-L-alaninyl)amino-2, 3-dihydro-l1-methyl-5-phenyl- 1H- 1,4-benzodiazepin-2-one ,4-dichlorophenoxy)butyryl)-L-alaninyl)amino-2 ,3dihydro-l1-methyl-5-phenyl- 1H- 1,4-benzodiazepin-2-one 3-dichlorophenoxyacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1methyl-5-phenyl-l1H-i ,4-benzodiazepin-2-one 3 -(4-chlorobenzoyl)propionyl)-L-alaninyl)amino-2 ,3-dihydro- 1 -methyl-5-phenyl- 1H- 1,4-benzodiazepin-2-one 2 -fluorophenylacetyl)-L-alaninyl)amino-2 ,3-dihydro-l1-methyl- 5-phenyl-1H- 1,4-benzodiazepin-2-one.
2 4 -cyanophenoxy)-2-methyl propionyl)-L-alaninyl)amino- 2, 3-dihydro-l1-methyl-5-phenyl- 1H-i ,4-benzodiazepin-2-one WO 98/28268 PCT/US97/22986 33 -(2-nitrophenylacetyl)-L-alaninyl)amino-2 ,3-dihydro-l1-methyl-5phenyl-1H-1 ,4-benzodiazepin-2-one 4 -(hydroxymethyl)phenoxyacety)-L-alaninyl)amino-2, 3dihydro-l1-methyl-5-phenyl- 1H- 1,4-benzodiazepin-2-one 2 -fluoro-3-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino- 2, 3-dihydro- 1 -methyl-5-phenyl- 1 H-i ,4-benzodiazepin-2-one 6-trifluorophenylacetyl)-L-alaninyl)amino-2, 3-dihydro- 1- 1H-i ,4-benzodiazepin-2-one 4 -fluoro-2-(trifluoromethyl)phenylacetyl)-L-alannyl)amino- 2, 3-dihydro- 1 -methyl-5-phenyl- 1 H-i ,4-benzodiazepin-2-one ,4-trifluorobutyryl)-L-alaninyl)amino-2 ,3-dihydro- 1methyl-5-phenyl-l1H-i ,4-benzodiazepin-2-one 2 -fluoro-4-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino- 2, 3-dihydro- 1 -metbyl-5-phenyl- 1H- 1 ,4-benzodiazepin-2-one '-(4-bromophenylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1i-methyl- 1H- 1,4-benzodiazepin-2-one 3 -(N'-(3-(4-fluorobenzoyl)propionyl)-L-alaninyl)amino.2 ,3-dihydro- 1 1H- 1,4-benzodiazepin-2-one 2 -methylphenoxy)acetyl)-L-alaniny)amino-2 ,3-dihydro- 1- 1 H-i ,4-benzodiazepin-2-one '-(4-methoxyphenoxyacetyl)-L-alaninyl)amino-2, 3-dihydro- 1methyl-S -phenyl- 1H- 1 ,4-benzodiazepin-2-one 3 -(phenylsulfonyl)propionyl)-L-alaninyl)amino-2, 3-dihydro- 1methyl-5-phenyl-1H-1 ,4-benzodiazepin-2-one 3 -(N'-(2-methoxyphenylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1- 1H-i ,4-benzodiazepin-2-one 2 -bromophenylacetyl)-L-alaninyl)amino-2, 3-dihydro-l1-methyl- 1H- 1 ,4-benzodiazepin-2-one '-(p-isopropylphenylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 iH-1 ,4-benzodiazepin-2-one 4 -pentenoyl)-L-alaninyl)amino-2 ,3-dihydro- 1H- 1 ,4-benzodiazepin-2-one WO 98t28268 PTU9/28 PCTIUS97/22986 34-- '-(4-hydroxyphenoxyacetyl)-L-alaniinyl)amino-2 ,3-dihydro- 1 methyl-5-phenyl-L1H-l ,4-benzodiazepin-2-one '-(4-oxopentanoyl)-L-alaninyl)amino-2, 3-dihydro- 1 phenyl- lH- 1,4-benzodiazepin-2-one (S)-3-(N'-(2-hydroxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro- I methyl-S -phenyl- 1 H-i ,4-benzodiazepin-2-one ,4-dimethoxyphenylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 1H- 1 ,4-benzodiazepin-2-one (S)-3-(N'-(3-(4-methoxybenzoyl)propionyl)-L-alaninyl)amino-2 ,3dihydro-I -methyl-5-phenyl-i1H- 1 ,4-benzodiazepin-2-one '-(thien-3-ylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 phenyl- 1H- 1,4-benzodiazepin-2-one '-(6-phenylhexanoyl)-L-alaninyl)amino-2 ,3-dihydro- 1 phenyl-lH- 1,4-benzodiazepin-2-one -(isovaleryl)-L-alaninyl)aniino-2 ,3-dihydro- 1 H-i ,4-benzodiazepin-2-one 5-trifluorophenylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 methyl-5-phenyl-l1H-i ,4-benzodiazepin-2-one 5-trifluorophenylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 methyl-5-phenyl-l1H-i ,4-benzodiazepin-2-one -adamantaneacetyl)-L-alaninyl)amino-2 ,3-dihydro-l1-methyl- 1H- 1,4-benzodiazepin-2-one (S)-3-(N'-(cyclohexanepentanoyl)-L-alaninyl)amino-2 ,3-dihydro- 1methyl-5-phenyl- 1 H-i ,4-benzodiazepin-2-one (S)-3-(N'-(2-thiopheneacetyl)-L-phenylglycinyl)amino-2 ,3-dihydro- 1- LH-1 ,4-benzodiazepin-2-one (S)-3-(N'-(3-(trifluoromethyl)phenylacetyl)-L-phenylglycinyl)amino-2, 3dihydro- 1-methyl-5-phenyl- 1H- 1 ,4-benzodiazepin-2-one ,5-difluorophenylacetyl)-L-phenylglycinyl)amino-2 .3- 1H-i ,4-benzodiazepin-2-one '-(3-tolylacetyl)-L-phenylglycinyl)amino-2 ,3-dihydro- 1 phenyl- LH- 1 ,4-benzodiazepin-2-one WO 98/28268 PCTIUS97/22986 35 '-(3-fluorophenylacetyl)-L-phenylglycinyl)amino-2 ,3-dihydro- 1 methyl-5-phenyl-l1H-i ,4-benzodiazepin-2-one -bromophenylacetyl)-L-phenylglycinyl)amino-2 ,3-dihydro- 1 methyl-5-phenyl- 1 H-i ,4-benzodiazepin-2-one '-(3-chlorophenylacetyl)-L-phenylglycinyl)amino-2 .3 -dihydro- 1 1H- 1 ,4-benzodiazepin-2-one ,4-methylenedioxyphenylacetyl)-L-phenylglycinyl)amino-2 ,3dihydro- 1-methyl-5-phenyl- 1H-i ,4-benzodiazepin-2-one '-(phenylmercaptoacetyl)-L-phenylglycinyl)amino-2 ,3-dihydro- 1 1H- 1 ,4-benzodiazepin-2-one -(acetyl)-L-phenylglycinyl)amino-2 ,3-dihydro- 1 phenyl- 1H-i ,4-benzodiazepin-2-one 2, 3-dihydro- 1 -methyl-5-phenyl- 1 H-i ,4-benzodiazepin-2-one '-((methylthio)acetyl)-L-phenylglycinyl)amino-2 ,3-dihydro- 1 methyl-5-phenyl-l1H-i ,4-benzodiazepin-2-one '-(phenoxyacetyl)-L-phenylglycinyl)amino-2 ,3-dihydro- i-methyl- H-i ,4-benzodiazepin-2-one '-(phenylacetyl)-L-phenylglycinyl)amino-2 ,3-dihydro-l1-methyl-5phenyl-l1H-i ,4-benzodiazepin-2-one '-(cyclohexylacetyl)-L-phenylglycinyl)amino-2 ,3-dihydro- 1 lH- 1,4-benzodiazepin-2-one ,5-difluorophenylacetyl)-L-phenylglycinyl)amino-2 ,3dihydro-l1-methyl-5-phenyl-l1H-i ,4-benzodiazepin-2-one (S)-3-(N'-(benzo[blthiophene-3-acetyl)-L-phenylglycinyl)amino-2 .3dihydro- 1-methyl-5-phenyl- 1H- 1,4-benzodiazepin-2-one -(benzoylformyl)-L-phenylglycinyl)amino-2 ,3-dihydro- 1 -methyl- 1H-i ,4-benzodiazepin-2-one ,6-difluorophenylacetyl)-L-phenylglycinyl)amino-2 ,3dihydro- 1 -methyl-5-phenyl- 1 H-i ,4-benzodiazepin-2-one 4 -difluorophenylacetyl)-L-phenylglycinyl)amino-2 ,3dihydro- 1 -methyl-5-phenyl- 1 H-i ,4-benzodiazepin-2-one WO 98/28268 PCTIUS97/22986 36-- ,4-difluorophenylacetyl)-L-phenylglycinyl)amino-2 .3- 1H- 1,4-benzodiazepin-2-one '-(butyryl)-L-phenylglycinyl)amino-2 ,3-dihydro- 1 phenyl- lH- 1,4-benzodiazepin-2-one -(heptanoyl)-L-phenylglycinyl)amino-2 ,3-dihydro- 1 phenyl- 1H- 1,4-benzodiazepin-2-one '-(4-(2-thienyl)butyryl)-L-phenylglycinyl)amino-2 ,3-dihydro- 1 1 H-i ,4-benzodiazepin-2-one '-(5-methylhexanoyl)-L-phenylglycinyl)amino-2 ,3-dihydro- 1- LH- 1,4-benzodiazepin-2-one -(hydrocinnamyl)-L-phenylglycinyl)amino-2 ,3-dihydro- 1 1H-i ,4-benzodiazepin-2-one '-(cyclopentylacetyl)-L-phenylglycinyl)amino-2 ,3-dihydro- 1 methyl-5-phenyl- 1H- 1,4-benzodiazepin-2-one '-(propionyl)-L-phenylglycinyl)amino-2 ,3-dihydro- 1 phenyl-l1H-i ,4-benzodiazepin-2-one 5-trifluorophenylacetyl)-L-phenylglycinyl)amino-2, 3- 1H-i ,4-benzodiazepin-2-one -(4-phenylbutyryl)-L-phenylglycinyl)amino-2 ,3-dihydro- 1- 1H- 1 ,4-benzodiazepin-2-one 3-(N '-(2-thiopheneacetyl)-L-alaninyl)amino-2 ,3-dihydro-5-phenyl- 1- (4,4 ,4-trifluorobutyl)- 1H- 1,4-benzodiazepin-2-one -(2-thiopheneacetyl)-L-alaninyl)amino-l1-(2-oxo-2-phenylethyl)-2 ,3dihydro-5-phenyl- 1 H-i ,4-benzodiazepin-2-one 3-(N '-(2-thiopheneacetyl)-L-alaninyl)amino- 1 -methyl-2 ,3-dihydro-5-(2thiazolyl)-l1H-i ,4-benzodiazepin-2-one 3-(N'-(2-thiopheneacetyl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1methyl-5-phenyl-l1H-i ,4-benzodiazepin-2-one 3-(N '-(2-thiopheneacetyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)- 2, 3-dihydro- 1 -methyl- I H-i ,4-benzodiazepin-2-one 3-(N '-(2-thiopheneacetyl)-L-alaninyl)amino-5-(2-thienyl)-2, 3-dihydro- 1 methyl-i H-i ,4-benzodiazepin-2-one WO 98t28268 PCT1US97/22986 37 3-(N '-(2-thiopheneacety)-L-alaninyl)amino-5-cyclohexy-2 3-dihydro- 1methyl-i H-i ,4-benzodiazepin-2-one -(2-thiopheneacetyl)-L-alaninyl)amino-7-bromo-5-(2-fluoropheny).
2, 3-dihydro- 1-methyl-i H-i ,4-benzodiazepin-2-one 3-(N '-(2-thiopheneacetyl)-L-alaninyl)-aniino-)-2 ,4-dioxo- 1 ,5-bis-(2 ,2diinethylpropyl)-2 ,3,4 ,5-tetrahydro- 1H- 1, 3-(N ,5-difluorophenylacetyl)-L-alaninyl)aniino-2 1 -(4,4,4-trifluorobutyl)- iH- 1,4-benzodiazepin-2-one ,5-difluorophenylacetyl)-L-alaninyl)amino-l1-(2-oxo-2phenylethyl)-2,3-dihydro-5-phenyl-iH- 1,4-benzodiazepin-2-one 3-(N ,5-difluorophenylacetyl)-L-alaninyl)amino-l1-methyl-2 ,3-dihydro- 5-(2-thiazolyl)- 1H-i ,4-benzodiazepin-2-one 3-(N ,5-difluorophenylacetyl)-L-alaninyl)amino-7-chloro-2 ,3-dihydro- 1 -methyl-5-phenyl- 1H- 1,4-benzodiazepin-2-one 3-(N ,5-difluorophenylacetyl)-L-alaninyl)amino-7-chloro-5-(2chlorophenyl)-2,3-dihydro- 1-methyl- iH- 1,4-benzodiazepin-2-one 3-(N ,5-difluorophenylacetyl)-L-alaninyl)amino-5-(2-thienyl)-2, 3dihydro- i-methyl-i H-i ,4-benzodiazepin-2-one 5-difluorophenylacetyl)-L-alaninyl)amino-5-cyclohexyl-2,3dihydro- i-methyl- iH- 1,4-benzodiazepin-2-one 3-N-35-difluorophenylacetyl)-L-alaninyl)amino-7-bromo-5-(2fluorophenyl)-2 ,3-dihydro- 1-methyl- iH- 1,4-benzodiazepin-2-one 3-(N ,5-difluorophenylacetyl)-L-alaninyl)-amino-)-2 ,4-dioxo- 1, (2 ,2-dimethylpropyl)-2 ,3 ,4,5-tetrahydro- iH- 3-(N '-(3-fluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-5-phenyl- 1- (4,4,4-trifluorobutyl)-l1H-i ,4-benzodiazepin-2-one 3-(N '-(3-fluorophenylacetyl)-L-alaninyl)amino-l1-(2-oxo-2-phenylethyl)- 2 ,3-dihydro-5-phenyl-l1H-i ,4-benzodiazepin-2-one 3-(N '-(3-fluorophenylacetyl)-L-alaninyl)amino-l1-methyl-2 (2-thiazolyl)-iH- 1,4-benzodiazepin-2-one 3-(N '-(3-fluorophenylacetyl)-L-aaniny)amino-7-chloro-2 ,3-dihydro- 1iH- 1,4-benzodiazepin-2-one WO 98/28268 PCT/EUS97/22986 38 3-(N '-(3-fluorophenylacetyl)-L-alaninyl)amino-7-chloro-5-(2chlorophenyl)-2 ,3-dihydro- 1 -methyl- 1H- 1 ,4-benzodiazepin-2-one 3-(N '-(3-fluorophenylacetyl)-L-alaninyl)amino-5-(2-thienyl)-2 ,3-dihydro- 1-methyl- 1 H-i ,4-benzodiazepin-2-one 3-(N '-(3-fluorophenylacetyl)-L-alaninyl)amino-5-cyclohexyl-2 ,3-dihydro- 1-methyl- lH- 1,4-benzodiazepin-2-one 3-(N'-(3-fluorophenylacetyl)-L-alaninyl)amino-7-bromo-5-(2fluorophenyl)-2 ,3-dihydro- 1-methyl- 1H- 1,4-benzodiazepin-2-one 3-(N'-(3-fluorophenylacetyl)-L-alaninyl)-amino-)-2 ,4-dioxo- 1 ,5-bis-(2 ,2dimethylpropyl)-2,3 5-tetrahydro- 1H- 3-(N '-(methylthio)acetyl)-L-alaninyl)amino-2, 3-dihydro-5-phenyl- 1- (4 ,4,4-trifluorobutyl)- 1H- 1,4-benzodiazepin-2-one 3-(N '-(methylthio)acetyl)-L-alaninyl)amino-l1-(2-oxo-2-phenylethyl)-2 ,3dihydro-5-phenyl-l1H-i ,4-benzodiazepin-2-one 3-(N '-(methylthio)acetyl)-L-alaninyl)amino- 1 -methyl-2 ,3-dihydro-5-(2thiazolyl)- 1H-i ,4-benzodiazepin-2-one 3-(N'-(methylthio)acetyl)-L-alaninyl)amino-7-chloro-2,3-dihydro- 1 iH- 1,4-benzodiazepin-2-one 3-(N '-(methylthio)acetyl)-L-alaninyl)amino-7-chloro-5-(2-chloropienyl)- 2, 3-dihydro- 1-methyl-i H-i ,4-benzodiazepin-2-one 3-(N'-(methylthio)acetyl)-L-alaninyl)amino-5-(2-thienyl)-2 ,3-dihydro- 1methyl-1H- 1,4-benzodiazepin-2-one -(methylthio)acetyl)-L-alaninyl)amino-5-cyclohexyl-2, 3-dihydro- 1 methyl-1H-1 ,4-benzodiazepin-2-one 3-(N '-(methylthio)acetyl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)- 2, 3-dihydro- 1-methyl- lH- 1,4-benzodiazepin-2-one 3-(N '-(methylthio)acetyl)-L-alaninyl)-amino-)-2 ,4-dioxo- 1 ,5-bis-(2,2dimethylpropyl)-2 5-tetrahydro-l1H-i 3-(N '-(phenylacetyl)-L-alaninyl)amino-2 ,3-dihydro-5-phenyl-l1-(4,4,4trifluorobutyl)- 1H- 1 ,4-benzodiazepin-2-one 3-(N '-(phenylacetyl)-L-alaninyl)amino-l1-(2-oxo-2-phenylethyl)-2 ,3- LH- 1,4-benzodiazepin-2-one WO 9812868 PCT/US97/22986 39 3-(N '-(phenylacetyl)-L-alaninyl)amin o-l1-methyl-2 ,3-dihydro-5-(2thiazoly iH- 1,4-benzodiazepin-2-one 3-(N '-(phenylacetyl)-L-alaninyl)amino-7-chloro-2,3-dihydro- 1 phenyl- 1H-i ,4-benzodiazepin-2-one 3-(N '-(phenylacetyI)- L-alaninyI)amino-7-chloro-5-(2-chloropheny)-2,3dihydro- 1-methyl-i H-i ,4-benzodiazepin-2-one 3-(N '-(phenylacetyl)-L-alaninyl)amino-5-(2-thienyl)-2, 3-dihydro- 1methyl-i H-i ,4-benzodiazepin-2-one 3-(N '-(phenylacetyl)-L-alaninyl)amino-5-cyclohexyl-2, 3-dihydro- 1methyl-i H-i ,4-benzodiazepin-2-one 3-(N'-(hnlctl -laiy~mn--rm-5(7loohnl ,3dihydro- i-methyl-i H-i ,4-benzodiazepin-2-one 3-(N'-(phenylacetyl)-L-alaninyl)-amino-)2,4-dioxo-i ,5-bis-(2,2dimethylpropyl)-2 ,3 ,4 ,5-tetrahydro-iH- 1, 3-(N '-(benzoylformyl)-L-alaninyl)amino-2 ,3-dihydro-5-phenyl-li-(4,4,4trifluorobutyl)-iH- 1,4-benzodiazepin-2-one 3-(N '-(benzoylformyl)-L-alaninyl)amino- 1 -(2-oxo-2-phenylethyl)-2 .3iH- 1 ,4-benzodiazepin-2-one 3-(N'-(benzoylformyl)-L-alaninyl)amino-i -methyl-2, 3-dihydro-5-(2thiazolyl)-liH-i ,4-benzodiazepin-2-one 3-(N'-(benzoylformyl)-L-alaninyl)amino-7-chloro-2 ,3-dihydro- i-methyliH-1i,4-benzodiazepin-2-one 3-(N '-(benzoylformyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2 ,3dihydro- i-methyl-LU-i ,4-benzodiazepin-2-one 3-(N '-(benzoylformnyl)-L-alaninyl)aniino-5-(2-thienyl)-2 ,3-dihydro- 1methyl-lH- 1,4-benzodiazepin-2-one 3-(N '-(benzoylformy1)-L-alaniny1)amino-5-cyclohexy-2 3-dihydro- 1methyl- iH-i ,4-benzodiazepin-2-one 3-(N'-(ezyfrnl)Laaiy~mno7boo5( .urpey)23dihydro- i-methyl- iH-1i,4-benzodiazepin-2-one 3-(N '-(benzoylformnyl)-L-alaninyl)-amino-)-2 ,4-dioxo- 1,5-bis-(2 .2dimethylpropyl)-2,3 5-tetrahydro- 1 H-i WO 98/28268 PCTIUS97/22986 40 3-(N'-(butyryl)-L-alaninyl)amino-2 ,3-dihydro-5-phenyl-l1-(4,4,4trifluorobutyl)- IH- 1 ,4-benzodiazepin-2-one 3-(N'-(butyryl)-L-alaninyl)amino-l1-(2-oxo-2-phenylethyl)-2 phenyl-iH-i ,4-benzodiazepin-2-one '-(butyryl)-L-alaninyl)amino-l1-methyl-2 ,3-dihydro-5-(2-thiazolyl)- IH- 1,4-benzodiazepin-2-one 3-(N'-(butyryl)-L- *alaninyl)amino-7-chloro-2 ,3-dihydro- phenyl- iH- 1,4-benzodiazepin-2-one ,3dihydro- 1-methyl- iH- 1,4-benzodiazepin-2-one 3-(N '-(butyry1)-L-alaniny1)amino-5-(2-thieny1)-2,3-dihydro- 1-methyl-i H- 1 ,4-benzodiazepin-2-one 3-(N'-(butyry1)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-i-methyl-i
H-
1 ,4-benzodiazepin-2-one 3-(N '-(butyry1)-L-alaninyl)amino-7-bromo-5-(2-fluoropienyl)-2,3dihydro- 1-methyl-i H-i ,4-benzodiazepin-2-one 3-(N'-(butyryl)-L-alaninyl)-amino-)-2 ,4-dioxo- 1,5-bis-(2 ,2diniethylpropyl)-2,3 ,4,5-tetrahydro-l1H-i 3-(N'-(4-(2-thienyl)butyryl)-L-alaninyl)amino-2 ,3-dihydro-5-phenyl- 1- (4,4 ,4-trifluorobutyl)-l1H-i ,4-benzodiazepin-2-one 3-(N '-(4-(2-thienyl)butyryl)-L-alaninyl)amino-l1-(2-oxo-2-phenylethyl)- 2, 3-dihydro-5-phenyl-ll-i ,4-benzodiazepin-2-one 3-(N '-(4-(2-thienyl)butyryl)-L-alaninyl)amino-l1-methyl-2 ,3-dihydro-5-(2thiazolyl)-iH-i ,4-benzodiazepin-2-one 3-(N '-(4-(2-thienyl)butyryl)-L-alaninyl)amino-7-chloro-2, 3-dihydro- 1iH- 1,4-benzodiazepin-2-one 3-(N'-(4-(2-thienyl)butyryl)-L-alaniny)amino-7-chloro-5-(2chlorophenyl)-2 ,3-dihydro- i-methyl- iH- 1,4-benzodiazepin-2-one 3-(N -4(-hey~uyrl--lnnlain--2tinl 3-dihydroi-methyl-i H-i ,4-benzodiazepin-2-one 3-(N 2 -thienyI)butyryl)-L-alaniny)amino-5-cyclohexyl-2 ,3-dihydro- 1-methyl-i H-i ,4-benzodiazepin-2 -one WO 98/28268 PCTUS97/22986 41 3-(N '-(4-(2-thienyl)butyry1)-L-alaniny1)amino-7-bromo-5-(2.
fluorophenyl)-2 ,3-dihydro- 1-methyl-i H-i ,4-benzodiazepin-2-one 3-(N '-(4-(2-thienyl)butyryl)-L-alaninyl)-amino-)-2 ,4-dioxo- 1, 5-bis-(2 ,2dimethylpropyl)-2 5-tetrahydro- 1 H-1, 3-(N '-(cyclopentylacetyl)-L-alaninyl)amino-2, 3-dihydro-5-phenyl- 1- (4,4 ,4-trifluorobutyl)- 1H-i ,4-benzodiazepin-2-one 3-(N '-(cyclopentylacetyl)-L-alaninyl)amino- 1 -(2-oxo-2-phenylethyl)-2 .3- 1H-i ,4-benzodiazepin-2-one 3-(N'-(cyclopentylacetyl)-L-alaninyl)amino- 1 -methyl-2,3-dihydro-5-(2thiazolyl)- iH-i ,4-benzodiazepin-2-one 3-(N '-(cyclopentylacetyl)-L-alaniryl)amino-7-chloro-2 ,3-dihydro- 1- 1H-i ,4-benzodiazepin-2-one 3-(N '-(cyclopentylacetyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)- 2, 3-dihydro- i-methyl- 1H- 1,4-benzodiazepin-2-one 3-(N '-(cyclopentylacetyl)-L-alaninyl)arnino-5-(2-thienyl)-2 ,3-dihydro- 1methyl- iH-1I,4-benzodiazepin-2-one 3-(N '-(cyclopentylacetyl)-L-alaninyl)amino-5 -cyclohexyl-2 ,3-dihydro- 1methyl- 1H- 1,4-benzodiazepin-2-one 3-(N '-(cyclopentylacetyl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)- 2,3-dihydro- I-methyl-i1H- 1,4-benzodiazepin-2-one N' -(cyclopentylacetyl)-L-alaninyl)-amino-)-2 ,4-dioxo- 1,5-bis-(2 ,2dimethylpropyl)-2 5-tetrahydro- 1H- 3-(N '-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-2 phenyl-li-(4 ,4,4-trifluorobutyl)-l1H-i ,4-benzodiazepin-2-one 3-(N '-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-l1-(2-oxo-2phenylethyl)-2 ,3-dihydro-5-phenyl- 1H- 1,4-benzodiazepin-2-one 3-(N '-(3-(trifluoromethyl)butyryl)-L-alaninyl)a miino- 1 -methyl-2, 3dihydro-5-(2-thiazolyl)- 1H- 1 ,4-benzodiazepin-2-one 3-(N '-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-7-chloro-2 ,3dihydro- i-methyl-5-phenyl- 1H- 1,4-benzodiazepin-2-one 3-(N '-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-7-chloro-5-(2chlorophenyl)-2 ,3-dihydro- 1 -methyl- I H-i ,4-benzodiazepin-2-one WO 98/28268 PCT/US97/22986 42-- 3-(N '-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-5-(2-thienyl)-2 ,3dihydro- i-methyl-i 1H-i ,4-benzodiazepin-2-one 3-(N '-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-5-cyclohexyl-2 ,3dihydro- 1-methyl-i 1H-i ,4-benzodiazepin-2-one 3-(N '-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-7-bromo-5-(2fluorophenyl)-2 ,3-dihydro- i-methyl-i H-i ,4-benzodiazepin-2-one 3-(N '-(3-(trifluoromethyl)butyryl)-L-alaninyl)-amino-)2 ,4-dioxo- (2 ,2-dimethylpropyl)-2 5-tetrahydro- 3-(N ,4-trifluorobutyryl)-L-alaninyl)ainino-2 ,3-dihydro-5-phenyl- 1 (4 ,4,4-trifluorobutyl)- iH-1i,4-benzodiazepin-2-one -(4,4,4-trifluorobutyryl)-L-alaninyl)amino- 1-(2-oxo-2-phenylethyl)-' 2 ,3-dihydro-5-phenyl-l1H-i ,4-benzodiazepin-2-one ,4-trifluorobutyryl)-L-alaninyl)amino-l1-methyl-2,3-dihydro-5- (2-thiazolyl)- iH- 1,4-benzodiazepin-2-one 3-(N ,4-trifluorobutyryl)-L-alaninyl)amino-7-chloro-2 3-dihydro- 1iH- 1,4-benzodiazepin-2-one 3-(N '-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-7-chloro-5-(2chlorophenyl)-2 ,3-dihydro- i-methyl- 1H- 1,4-benzodiazepin-2-one 3-(N '-(4,4,4-trifluorobutyryl)-L-alaninyl)anino-5-(2-thienyl)-2 .3dihydro- i-methyl-i H-i ,4-benzodiazepin-2-one 3-(N ,4,4-trifluorobutyryl)-L-alaninyl)amino-5-cyclohexyl-2, 3dihydro- i-methyl-i H-i ,4-benzodiazepin-2 -one -(4,4,4-trifluorobutyryl)-L-alaninyl)amino-7-bromo-5-(2fluorophenyl)-2 ,3-dihydro- I -methyl- IH- 1 ,4-benzodiazepin-2-one ,4-trifluorobutyryl)-L-alaninyl)-amino-)-2 ,4-dioxo- 1, 5-bis-(2 .2dimethylpropyl)-2 ,3 5-tetrahydro- 1H-i, 3-(N '-(isovaleryl)-L-alaninyl)amino-2 ,3-dihydro-5-phenyl-l1-(4,4,4trifluorobutyl)- iH- 1,4-benzodiazepin-2-one -(isovaleryl)-L-alaninyl)amino- i-(2-oxo-2-phenylethyl)-2 ,3-dihydro- 5-phenyl-l1H-i ,4-benzodiazepin-2-one 3-(N '-(isovaleryl)-L-alaninyl)amino-l1-methyl-2 ,3-dihydro-5-(2-thiazolyl)- 1 H-i ,4-benzodiazepin-2-one WO 98/28268 PC'r1US97/22986 43 3-(N '-(isovaleryl)-L-alaninyl)amino-7-chloro-2 ,3-dihydro- 1 phenyl-lIH- 1 ,4-benzodiazepin-2-one 3-(N '-(isovalery1)-L-alaninyl)amino-7-chloro-5-(2-chloropheny)-2 ,3dihydro- 1-methyl-i H-i ,4-benzodiazepin-2-one 3-(N '-(isovaleryl)-L-alaninyl)amino-5-(2-thienyl)-2, 3-dihydro-l1-methyl- 1 H-i ,4-benzodiazepin-2-one 3-(N '-(isovaleryl)-L-alaninyl)amino-5-cyclohexyl-2, 3-dihydro- 1 -methyl- LH-i ,4-benzodiazepin-2-one 3-(N '-(isovaleryl)-L-alaninyI)amino-7-bromo-5-(2-fluorophenyI)-2 .3dihydro- 1 -methyl- 111-i ,4-benzodiazepin-2-one 3-(N '-(isovaleryl)-L-alaninyl)-amino-)-2 ,4-dioxo- 1, 5-bis-(2 ,2dimethylpropyl)-2,3,4 ,5-tetrahydro- 1H-i -(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-2 phenyl-li-(4 ,4,4-trifluorobutyl)-liH-i ,4-benzodiazepin-2-one 3-(N '-(L-alpha-hydroxyisocaproyl)-L-alaninyl)ammno- 1 -(2-oxo-2phenylethyl)-2 ,3-dihydro-5-phenyl- 1 H-i ,4-benzodiazepin-2-one* 3-(N '-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-l1-methyl-2 ,3dihydro-5-(2-thiazolyl)-l1H-i ,4-benzodiazepin-2-one 3-(N '-(L-alpha-hydroxyisocaproyl)-L-aianinyl)amino-7-chloro-2 ,3dihydro- I-methyl-5-phenyl- 1H- 1 ,4-benzodiazepin-2-one 3-(N '-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-7-chloro-5-(2chlorophenyl)-2, 3-dihydro- 1 -methyl-i1 H-i ,4-benzodiazepin-2-one 3-(N '-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amrno-5-(2-thienyl)-2 ,3dihydro- 1 -methyl- 1H- 1 ,4-benzodiazepin-2-one 3-(N '-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-5-cyclohexyl-2, 3dihydro- 1-methyl- iH- 1,4-benzodiazepin-2-one 3-(N '-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-7bromo-5(2fluorophenyl)-2 ,3-dihydro- I -methyl- 1H- 1 ,4-benzodiazepin-2-one 3-(N '-(L-alpha-hydroxyisocaproyl)-L-alaninyl)-amino-)2 ,4-dioxo- bis-(2 ,2-dimethylpropyl)-2 5-tetrahydro- 1 H-i 3-(N +)-mandelyl)-L-alaninyl)amino-2 ,3-dihydro-5-phenyl- 1 trifluorobutyl)-1 H- 1 ,4-benzodiazepin-2-one WO 98/28268 PTU9128 PCTIUS97/22986 44-- +)-mandelyl)-L-alaninyl)amino- 1-(2-oxo-2-phenylethyl)-2 .3iH-i ,4-benzodiazepin-2-one 3-(N +)-mandelyl)-L-alaninyl)amino-l1-methyl-2 ,3-dihydro-5-(2thiazolyl)- 1H- 1 ,4-benzodiazepin-2-one 3-(N +)-mandelyl)-L-alaninyl)amino-7-chloro-2.3 -dihydro-1 1H-i ,4-benzodiazepin-2-one 3-(N +)-mandelyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)- 2, 3-dihydro- 1-methyl- 1H- 1,4-benzodiazepin-2-one 3-(N +)-mandelyl)-L-alaninyl)amino-5-(2-thienyl)-2 ,3-dihydro- 1 methyl- lH- 1,4-benzodiazepin-2-one 3-(N +)-mandelyl)-L-alaninyl)amino-5-cyclohexyl-2 ,3-dihydro- 1 methyl- 111- 1,4-benzodiazepin-2-one 3-(N +)-mandelyl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)- 2, 3-dihydro- 1 -methyl-i1 H-i ,4-berizodiazepin-2-one 5-difluoropheny lacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1-(3-fluorobenzyl)- 11-1 ,4-benzodiazepin-2-one 5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1 -(benzy IH- 1 ,4-benzodiazepin-2-one 3-(N ,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1 -(4-tert-butylbenzyl)- 1H- 1 ,4-benzodiazepin-2-one ,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1 -(2-cyclohexylethyl)- iH- 1,4-benzodiazepin-2-one 3-(N ,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1 3-dimethylbutyl)- iH- 1,4-benzodiazepin-2-one 3-(N 5-difluorophenylacetyl)-L-alaninyl)aniino-5-phenyl-2.3 -dihydro- 1 -methoxycarbonyl- 1 -phenylmethyl)- 1 H-i ,4-benzodiazepin-2-one 3-(N -difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1 -(2-ethylbutyl)- 1 H-i ,4-benzodiazepin-2-one 3-(N 5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro- 1 -(cyclohexylmethyl)- 1H- 1,4-benzodiazepin-2-one 3-(N ,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2, 3-dihydro- 1 -(2-phenylethyl)- 1 H-i ,4-benzodiazepin-2-one WO 98/28268 WO 9828268PCT/US97/22986 45 3-(N 5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1 -(3-phenyipropyl)- 1H- 1,4-benzodiazepin-2-one 3-(N 5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1 -(2-(N-phthalimidyl)ethyl)-l1H-i ,4-benzodiazepin-2-one 3-(N ,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1 -(2-biphenylmethyl)- 1H-i ,4-benzodiazepin-2-one ,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1-((2-tetrahydrofuranyl)methyl)- 1H- 1 ,4-benzodiazepin-2-one 3-(N ,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2, 3-dihydro- 1 ,4-benzodioxanyl)methyl)- 11-1 ,4-benzodiazepin-2-one 3-(N 5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1 -(3-(5-chlorobenzo[b] thienyl)methyl)-l1H-i ,4-benzodiazepin-2-one 3-(N ,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1-(3 ,3-dimethyl-2-oxo-propyl)- 1H- 1,4-benzodiazepin-2-one 3-(N 5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2, 3-dihydro- 1 -(5-benzofurazanylmethyl)- 1H- 1,4-benzodiazepin-2-one 3-(N ,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1 -(3-phenoxypropyl)- 1H- 1,4-benzodiazepin-2-one 3-(N ,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1-(6-(2-trifluoromethylquinolinyl)methyl)- LH-1 ,4-benzodiazepin-2-one 3-(N ,5-difluorophenylacetyl)-L-alaninyl)axnino-5-phenyl-2 ,3-dihydro- 1 -(2-methylbutyl)-l1H-i ,4-benzodiazepin-2-one 3-(N ,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1 -ethyl- 1H- 1 ,4-benzodiazepin-2-one 3-(N ,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1 -(3-pyridylmethyl)-l1H-i ,4-benzodiazepin-2-one 3-(N 5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1 -(2-oxo-2-(N-indolinyl)ethyl)- 1H-i ,4-benzodiazepin-2-one 3-(N 5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1 ,5-dimethylisoxazolyl)methyl)-l1H-i ,4-benzodiazepin-2-one ,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1 -(2-methoxyethyl)- lH- 1,4-benzodiazepin-2-one WO 98/28268 PCT/US97/22986 46 3-(N '-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1- (benzyl)-1H- 1 ,4-benzodiazepin-2-one -(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1 tert-butylbenzyl)- 1 H-i ,4-benzodiazepin-2-one 3-(N '-.(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2, 3-dihydro-l1-(2cyclohexylethyl)- 1H-i ,4-benzodiazepin-2-one 3-(N '-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1 dimethylbutyl)-l1H-i ,4-benzodiazepin-2-one 3-(N '-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1- (isopropy 1)-iH-i ,4-benzodiazepin-2-one 3-(N '-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2, 3-dihydro-l1-(1methoxycarbonyl- 1 -phenylmethyl)- 1 H-i ,4-benzodiazepin-2-one 3-(N '-(cyclopentylacetyl)-L-alaninyl)atnino-5-phenyl-2, 3-dihydro-l1-(2ethylbutyl)- 1H-i ,4-benzodiazepin-2-one 3-(N '-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2, 3-dihydro- 1- (cyclohexylmethyl)-l1H-i ,4-benzodiazepin-2-one 3-(N '-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1 phenylethyl)- 1 H-i ,4-benzodiazepin-2-one 3-(N '-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro-l1-(3phenyipropyl)-l1H-i ,4-benzodiazepin-2-one 3-(N '-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro-l1-(2- (N-phthalimidyl)ethyl)- iH- 1,4-benzodiazepin-2-one 3-(N '-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2.3 -dihydro-l1-(2biphenylmethyl)- 1 H-i ,4-benzodiazepin-2-one 3-(N '-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2 3-dihydro- 1 chlorobenzo[b] thienyl)methyl)- lH- 1,4-benzodiazepin-2-one -(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2, 3-dihydro-l1-(3,3dimethyl-2-oxo-butyl)- 1H-i ,4-benzodiazepin-2-one 3-(N '-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2, 3-dihydro- 1 benzofurazanylmethyl)-l1H-i ,4-benzodiazepin-2-one -(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro-l1-(3phenoxypropy iH- 1,4-benzodiazepin-2-one WO 98/28268 PCTIUS97/22986 47 3-(N '-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1 trifluoromethylquinolinyl)methyl)- 1 H-i ,4-benzodiazepin-2-one 3-(N '-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1- (cyclopropylmethyl)- LH- 1,4-benzodiazepin-2-one 3-(N '-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2, 3-dihydro- 1 methylbutyl)-l1H-i ,4-benzodiazepin-2-one 3-(N'-(cyclop entylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1 -ethyl- 1H- 1 ,4-benzodiazepin-2-one 3-(N '-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1 5-dixnethylisoxazolyl)methyl)-l1H-i ,4-benzodiazepin-2-one 3-(N '-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3 -dihydro- 1 propyl- 1H- 1,4-benzodiazepin-2-one 3-(N '-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro-l1-(2methoxyethyl)- lH- 1,4-benzodiazepin-2-one 3-(N ,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2, 3 -dihydro- 1 (benzyl)-1H- 1,4-benzodiazepin-2-one 3-(N '-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1- (4-tert-butylbenzyl)- 1 H-i ,4-benzodiazepin-2-one 3-(N '-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-pheny1-2 ,3-dihydro- 1 (2-cyclohexylethyl)- 1 H-i ,4-benzodiazepin-2-one 3-(N ,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro-lI- (3 ,3-diniethylbutyl)- 1H-1I,4-benzodiazepin-2-one 3-(N '-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1- (isopropyl)-1H- 1,4-benzodiazepin-2-one 3-(N ,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2, 3-dihydro- 1- (1 -methoxycarbonyl- 1 -phenylmethyl)- 1 H-i ,4-benzodiazepin-2-one 3-(N ,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2, 3-dihydro- 1- (2-ethylbutyl)-l1H-i ,4-benzodiazepin-2-one 3-(N ,4-trifluorobutyryl)-L-alaninyl)amino-5-pheny.2 3-dihydro- 1 (cyclohexylmethyl)- 1H- 1 ,4-benzodiazepin-2-one 3-(N ,4-trifluorobutyryl)-L-alaninyl)amino-5-pienyl-2 ,3-dihydro- 1 (3-phenylpropyl)-l1H-i ,4-benzodiazepin-2-one WO 98/28268 PCT1US97/22986 48 3-(N ,4,4-trifluorobutyryl)-L-alaninyl)amino-5-pheny-2 3-dihydro- 1- (2-biphenylmethyl)- 1 H-i ,4-benzodiazepin-2-one 3-(N '-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2, 3-dihydro- 1- (3-(5-chlorobenzo[b] thienyl)methyl)-l1H-i ,4-benzodiazepin-2-one 3-(N ,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2, 3-dihydro- 1 (3 ,3-dimethyl-2-oxo-butyl)-iH-i ,4-benzodiazepin-2-one 3-(N ,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1- (5-benzofurazanylmethyl)-1IH- 1,4-benzodiazepin-2-one 3-(N ,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2.3 -dihydro- 1- (3-phenoxypropyl)- 1H- 1,4-benzodiazepin-2-one 3-(N ,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2 3-dihydro- 1- (6-(2-trifluoromethylquinolinyl)methyl)- 1 H-i ,4-benzodiazepin-2-one 3-(N ,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1- (cyclopropylmethy 1)-i H-i ,4-benzodiazepin-2-one 3-(N '-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-pheny1-2 ,3-dihydro- 1- (2-methylbutyl)-l1H-i ,4-benzodiazepin-2-one 3-(N '-(4,4,4-trifluorobutyryl)-L-alaninyl)amiiino-5-phenyl-2 ,3-dihydro- 1- (ethyl)-i1H- 1 ,4-benzodiazepin-2-one 3-(N '-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2, 3-dihydro- 1- ,5-dimethylisoxazolyl)methyl)- 1 H-i ,4-benzodiazepin-2-one 3-(N ,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1- (propy1)-i H-i ,4-benzodiazepin-2-one 3-(N ,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2, 3-dihydro- 1 (2-methoxyethyl)- iH-i ,4-benzodiazepin-2-one N' +)-mandelyl)-L-alaninyl)-amino-)-2 ,4-dioxo- 1,5-bis-(2 ,2dimethylpropyl)-2 5-tetrahydro-l1H-i -(N-pyrrolidinylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1-methyl- 1,4-benzodiazepin-2-one 3-(N 2 -chlorophenoxyacetyl)-L-alaninyl)amino-2 ,3-dihydro-l1-methyl-5phenyl- 1H-i ,4-benzodiazepin-2-one 3-(N '-(2-thiopheneacetyl)-L-aianinyl)amino-2 ,3-dihydro- 1 phenyl -IH-i 4 -benzodiazepin-2-one WO 98/28268 P~U9128 PCTIIJS97/22986 49 3-(N '-(3-(trifluoromethyl)phenylacetic)-L-alaninyl)amino-2 ,3-dihydro- 1 -1H- 1,4-benzodiazepin-2-one 3-(N '-(4-tolylacetyl)-L-alaninyl)amino-2, 3-dihydro- 1-methyl-5-phenyI 1H-1 ,4-benzodiazepin-2-one 3-(N '-(3-(4-methoxyphenyl)propionyl)-L-alaninyl)amino-2 ,3-dihydro- 1- 1H- 1,4-benzodiazepin-2-one 3-(N 5-difluorophenylacetyl)-L-alaninyl)amino-2 ,3-dihydro-l1-methyl- 5-phenyl-l11-1 ,4-benzodiazepin-2-one 3-(N '-(m-tolylacetyl)-L-alaninyl)amino-2, 3-dihydro-l1-methyl-5-phenyl- LH- 1,4-benzodiazepin-2-one 3-(N '-(3-fluorophenylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 phenyl-l1H-i ,4-benzodiazepin-2-one 3-(N '-(3-bromophenylacetyl)-L-alaninyl)amino-2, 3-dihydro- 1 phenyl- 1H-i ,4-benzodiazepin-2-one 3-(N '-(4-chlorophenoxyacetyl)-L-alaninyl)amino-2, 3-dihydro-l1-methyl-5phenyl-I1H-i ,4-benzodiazepin-2-one 3-(N '-(2-naphthylacetyl)-L-alaninyl)amino-2 ,3-dihydro-l1-methyl-5phenyl- lH- 1,4-benzodiazepin-2-one -(3-methylphenoxyacetyl)-L-alaninyl)amino-2, 3-dihydro- 1 phenyl-l1H-i ,4-benzodiazepin-2-one '-(4-methoxyphenylacetyl)-L-alaninyl)amino] 3-dihydro- 1-methyl- 5-(2-pyridyl)- I1H- 1,4-benzodiazepin-2-one 3-('-(2-thiopheneacetyl)-L-alaninyl)amino] 3-dihydro- 1 -methyl-5-(2pyridyl)- 1H- 1,4-benzodiazepin-2-one 5-difluorophenylacetyl)-L-alaninyl)amino] -2 ,3-dihydro- 1methyl-5-(2-pyridyl)- lH- 1,4-benzodiazepin-2-one '-(3-bromophenylacetyl)-L-alaninyl)amino]-2 ,3-dihydro-l1-methyl-5- (2-pyridyl)-1H- 1,4-benzodiazepin-2-one '-(phenylmercaptoacetyl)-L-alaninyl)amino)-2, 3-dihydro- 1-methyl- 5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one '-(4-ethoxyphenylacetyl)-L-alaninyl)aminol-2 ,3-dihydro- (2-pyridyl)-lH- 1, 4 -benzodiazepin-2-one WO 98=8268 PTU9128 PCTIUS97/22986 50 3- -(4-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino]-2 ,3-dihydro- 1 -methyl-5-(2-pyridyl)-1IH- 1,4-benzodiazepin-2-one 3 5-bis(trifluoromethyI)phenylacety)-L-alaninyl)amino-2 ,3dihydro-l1-methyl-5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2-one -((methylthio)acetyl)-L-alaninyl)amino]-2 ,3-dihydro- 1 -methyl-5-(2pyridy lH- 1,4-benzodiazepin-2-one 3- -(cyclohexylacetyl)-L-alaminyl)amino] 3-dihydro- 1-methyl-5-(2pyridyl)- 1H-i ,4-benzodiazepin-2-one 3- -(pentafluorophenoxyacetyl)-L-alaninyl)amino] 3-dihydro- 1methyl-5-(2-pyridyl)-1H- 1,4-benzodiazepin-2-one 3- -(benzo[b]thiophene-3-acetyl)-L-alaninyl)amino]-2 ,3-dihydro- 1 methyl-5-(2-pyridyl)- 11-1 ,4-benzodiazepin-2-one '-(2,4,6-trimnethylphenylacetyl)-L-alaninyl)amino] 3-dihydro- 1 methyl-5-(2-pyridyl)- 1H- 1,4-benzodiazepin-2-one 3- '-(4-biphenylacetyl)-L-alaninyl)amino] 3-dihydro-l1-methyl-5-(2pyridyl)- I1H- 1 ,4-benzodiazepin-2-one 3- ,4-difluorophenylacetyl)-L-alaninyl)amino] 3-dihydro- 1methyl-5-(2-pyridyl)- LH- 1 ,4-benzodiazepin-2-one 3- -(4-(2-thienyl)butyryl)-L-alaninyl)amino] 3-dihydro- 1 (2-pyridyl)- 1H- 1,4-benzodiazepin-2-one 3- '-(5-methylhexanoyl)-L-alaninyl)amino]-2 ,3-dihydro- 1 -methyl-5-(2pyridyl)- 1H- 1 ,4-benzodiazepin-2-one 3- '-(3-methoxycarbonylpropionyl)-L-alaninyl)amino] 3-dihydro- 1 methyl-5-(2-pyridyl)-1H-1 ,4-benzodiazepin-2-one 3- ,6-difluoromanclelyl)-L-alaninyl)amino] (2-pyridyl)- 1H-i ,4-benzodiazepin-2-one '-(4-fluoromandelyl)-L-alaninyl)amino] -2 ,3-dihydro-l1-methyl-5-(2pyridyl)- 1 H-i ,4-benzodiazepin-2-one 3- 5-difluoromandelyl)-L-alaninyl)amino] 3-dihydro-l1-methyl-5- (2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3- 6-trifluorophenylacetyl)-L-alaninyl)aminoj 3-dihydro- 1 methyl-5-(2-pyridyl)- 1H- 1 4-benzodiazepin-2-one WO 98t28268 PCT/US97/22986 51 '-(4-fluoro-2-(trifluoromethyl)phenylacetyl)-L-alaninyl)aminoj -2,3dihydro-l1-methyl-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one ,4-trifluorobutyryl)-L-alaninyl)aminoj-2 ,3-dihydro-l1-methyl- 5-(2-pyridyl)-1H-1 ,4-benzodiazepin-2-one 3- '-(4-isopropylphenylacetyl)-L-alaninyl)amino] 3-dihydro- 1methyl-5-(2-pyridyl)- 1H- 1 ,4-benzodiazepin-2-one 3-[(N'-(beta-phenyllactyl)-L-alaninyl)amino]-2 ,3-dihydro-l1-methyl-5-(2pyridyl)- 1 H-i ,4-benzodiazepin-2-one '-(mandelyl)-L-alaninyl)amino] -2 .3-dihydro- 1 -methyl-5-(2-pyridyl)- 1 H-i ,4-benzodiazepin-2-one '-(4-chloromandelyl)-L-alaninyl)aminoj 3-dihydro-l1-methyl-5-(2pyridyl)- 1H-i ,4-benzodiazepin-2-one '-(isovaleryl)-L-alaninyl)aminol-2 ,3-dihydro- 1-methyl-5-(2-pyridyl)- 1H-1 ,4-benzodiazepin-2-one 5-trifluorophenylacetyl)-L-alaninyl)amino] 3-dihydro- 1methyl-5-(2-pyridyl)-l1H-I ,4-benzodiazepin-2-one 3-[(N'-(3-methylthiopropionyl)-L-alaninyl)amino] 3-dihydro- 1-methyl- 5-(2-pyridyl)-1H- 1,4-benzodiazepin-2-one '-(L-alpha-hydroxyisocaproyl)-L-alaninyl)aminol 3-dihydro- 1 methyl-5-(2-pyridyl)- 1H-1 ,4-benzodiazepin-2-one 3[N-(3-nitrophenylacetyl)-L-alaninyl)amino] 3-dihydro-l1-methyl-5- (2-pyridyl)- 1H- 1,4-benzodiazepin-2-one 3- '-(D-3-phenyllactyl)-L-alaninyl)amino] 3-dihydro- 1 -methyl-5-(2pyridyl)-1H- 1,4-benzodiazepin-2-one 3-[(N'-(4-methocyphenylacetyl)-L-alaninyl)amino] 3-dihydro- 1 dimethyl-2-oxobutyl)- 5-(2-pyridyl)- 1H- 1,4-benzodiazepin-2-one '-(2-thiopheneacetyl)-L-alaninyl)aminoj-2.3 -dihydro-l1-(3,3dimethyl-2-oxobutyl)- 5-(2-pyridyl)- LH- 1,4-benzodiazepin-2-one 3[N-(3 ,5-difluorophenylacetyl)-L-alaninyl)amino] 3-dihydro-l1-(3,3dimethyl-2-oxobutyl)- 5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2-one 3- -(3-bromophenylacetyl)-L-alaninyl)amino] 3-dihydro-l1-(3,3dimethyl-2-oxobutyl)- 5-(2-pyridyl)- 1H- 1,4-benzodiazepin-2-one WO 98/28268 PCTJUS97122986 52 '-(phenylmercaptoacetyl)-L-alaninyl)anino 3-dihydro-l1-(3,3dimethyl-2-oxobutyl)- 5-(2-pyridyl)- 1H-i 4 -benzodiazepin-2-one 3[N-(4-ethoxyphenylacetyl)-L-alaninyl)amino] 3-dihydro-l1-(3,3dimethyl-2-oxobutyl)- 5-(2-pyridyl)- lH- 1,4-berizodiazepin-2-one '-(4-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino] 3-dihydro- 1 3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2-one ,5-bis(trifluoromethyl)phenylacetyl)-L-alaninyl)amino..2,3dihydro-l1-(3, 3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-l1H- 1,4benzodiazepin-2-one 3- -((methylthio)acetyl)-L-alaninyl)amino]-2 ,3-dihydro-l1-(3,3dimethyl-2-oxobutyl)- 5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3[N-(cyclohexylacetyl)-L-alaninyl)amino] 3-dihydro-l1-(3 ,3-dimnethyl- 2-oxobutyl)- 5-(2-pyridyl)-1H- 1,4-benzodiazepin-2-one '-(pentafluorophenoxyacetyl)-L-alaninyl)amino] 3-dihydro-l1-(3,3dimethyl-2-oxobutyl)- 5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3-('-(benzo[b]thiophene-3-acetyl)-L-alaninyl)amino]-2,.3-dihydro- 1- 3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3- ,4,6-trimethylphenylacetyl)-L-alaninyl)amino]-2 ,3-dihydro- 1- 3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2-one -(4-biphenylacetyl)-L-alaninyl)amino] 3-dihydro-l1-(3, 3-dimethyl- 2-oxobutyl)- 5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2-one ,4-difluorophenylacetyl)-L-alaninyl)aniino]-2 ,3-dihydro- 1 dimethyl-2-oxobutyl)- 5-(2-pyridyl)- 1H-i, 4-benzodiazepin-2-one '-(4-(2-thienyl)butyl)-L-alaninyl)amino] -2 ,3-dihydro-l1-(3,3dimethyl-2-oxobutyl)- 5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2-one 3- '-(5-methylhexanoyl)-L-alaninyl)amino]-2,3-dihydro- 1-(3,3dimethyl-2-oxobutyl)- 5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3- ,6-difluoromandelyl)-L-alaninyl)amino]-2 ,3-dihydro-l1-(3,3dimethyl-2-oxobutyl)- 5-(2-pyridyl)- 1H-i, 4-benzodiazepin-2-one 3- -(4-fluoromandelyl)-L-alaninyl)amino] 3-dihydro-l1-(3,3dimethyl-2-oxobutyl)- 5-(2-pyridyl)- iH- 1,4-benzodiazepin-2-one WO 98/28268 PCT/US97/22986 53 3- ,5-difluoromandelyl)-L-alaninyl)amino] 3-dihydro-l1-(3,3dimethyl-2-oxobutyl)- 5-(2-pyridyl)- 11-1 4 -benzodiazepin-2-one 3- 6-trifluorophenylacetyl)-L-alaninyl)amino]-2 3 -dihydro- 1- 3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2-one 4 -fluoro-2-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino] -2,3dihydro- 3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-l1H- 1,4berizodiazepin-2-one ,4-trifluorobutyryl)-L-alaninyl)amino]-2 ,3-dihydro- 1 dimethyl-2-oxobutyl)- 5 -(2-pyridyl)- 1H-i, 4-benzodiazepin-2-one -(4-isopropylphenylacetyl)-L-alaninyl)axnino]-2 ,3-dihydro-l1-(3,3dimethyl-2-oxobutyl)- 5-(2-pyridyl)-iH- 1, 4-benzodiazepin-2-one -(beta-phenyllactyl)-L-alaninyl)amino]-2 ,3-dihydro- 1 diinethyl-2-oxobutyl)- 5-(2-pyridyl)- 1H- 1,4-benzodiazepin-2-one '-(mandelyl)-L-alaninyl)amino]-2 ,3-dihydro- 1 3-dimethyl-2oxobutyl)- 5-(2-pyridyl)-iH- 1,4-benzodiazepin-2-one 3[N-(4-chloromandelyl)-L-alaninyl)amino] 3-dihydro- 1 dimethyl-2-oxobutyl)- 5-(2-pyridyl)- 1H-i, 4-benzodiazepin-2-one '-(isovaleryl)-L-alaninyl)amino] 3-dihydro-l1-(3, 3-dimethyl-2oxobutyl)- 5-(2-pyridyl)- 1H- 1,4-benzodiazepin-2-one 3- ,5-trifluorophenylacetyl)-L-alaninyl)amino] -2,3 -dihydro- 1- 3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one '-(3-methylthiopropionyl)-L-alaninyl)amino] 3-dihydro-l1-(3,3dimethyl-2-oxobutyl)- 5-(2-pyridyl)-l11-1 ,4-benzodiazepin-2-one '-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino]-2 ,3-dihydro- 1- (3 ,3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one -(3-nitrophenylacetyl)-L-alaninyl)aminol-2 ,3-dihydro-l1-(3,3dimethyl-2-oxobutyl)-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3 -phenyllactyl)-L-alaninyl)amino]-2 ,3-dihydro-l1-(3, 3-dimethyl- 2-oxobutyl)-5-(2-pyridyl)- lH- 1,4-benzodiazepin-2-one 4 -methoxyphenylacetyl)-L-alaninyl)amino]-2 ,3-dihydro-l1-(2-N, Ndiethyl aminoethyl)-5-(2-pyridyl)- 11-1 ,4-benzodiazepin-2-one WO 98/28268 PCT/US97/22986 54-- 3- -(2-thiopheneacetyl)-L-alaninyl)amino]-2, 3-dihydr&' 1 Ndiethylaminoethyl)-5-(2-pyridyl)- 1LH- 1 ,4-benzodiazepin-2-one -acetyl-N "-phenylglycinyl)L-alaninyl)amino] 3-dihydro-l1-(2- N, N-diethyl aminoethyl)- 5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one ,5-difluorophenylacetyl)-L-alaninyl)amino -2 ,3-dihydro-l1-(2- N, N-diethyl aminoethyl)- 5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3-[(N'-(3-bromophenylacetyl)-L-alaninyl)amino] 3-dihydro-l1-(2-N ,Ndiethyl aminoethyl)- 5-(2-pyridyl)-l11-1 ,4-benzodiazepin-2-one 3-('-(phenylmercaptoacetyl)-L-alaninyl)amino] 3-dihydro-l1-(2-N, Ndiethyl aminoethyl)- 5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one '-(4-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino] 3-dihydro- 1 N-diethyl aminoethyl)- 5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one.
3- ,5-bis(trifluoromethyl)phenylacetyl)-L-alaninyl)aininoj-2 .3dihydro-l1-(2-N, N-diethyl aminoethyl)- 5-(2-pyridyl)- 1H- 1,4benzodiazepin-2-one '-(cyclohexylacetyl)-L-alaninyl)amino]-2 ,3-dihydro-l1-(2-N, Ndiethyl aminoethyl)- 5-(2-pyridyl)- lH-1 ,4-benzodiazepin-2-one 3- '-(pentafluorophenoxyacetyl)-L-alaninyl)amino] 3-dihydro- 1-(2- N ,N-diethyl aminoethyl)- 5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2-one 3- -(benzo[blthiophene-3-acetyl)-L-alaninyl)amino] 3-dihydro-l1-(2- N, N-diethyl aminoethyl)- 5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2-one 3- -(benzoylformyl)-L-alaninyl)amino] 3-dihydro-l1-(2-N, N-diethyl aminoethyl)- 5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one ,4-difluorophenylacetyl)-L-alaninyl)aminol 3-dihydro-l1-(2- N ,N-diethyl aminoethyl)- 5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3- '-(4-(2-thienyl)butyryl)-L-alaninyl)amino] 3-dihydro- Ndiethyl aininoethyl)- 5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one '-(5-methylhexanoyl)-L-alaninyl)amino]-2 ,3-dihydro-l1-(2-N, Ndiethyl aminoethyl)- 5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3[N-(4-fluoromandelyl)-L-alaninyl)amino] 3-dihydro-l1-(2-N, Ndiethyl aminoethyl)- 5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2-one WO 98/28268 PCT/US97/22986 55 ,5-difluoromandelyl)-L-alaninyl)amino]-2 ,3-dihydro-l1-(2-N, Ndiethyl aminoethyl)- 5-(2-pyridyl)- 1H-i 4 -benzodiazepin-2-one 3-[(N'-(4,4,4-trifluorobutyryl)-L-alaninyl)aminoj.2 ,3-dihydro-l1-(2-N, Ndiethyl aminoethyl)- 5-(2-pyridyl)-1H-1 ,4-benzodiazepin-2-one 4 -isopropylphenylacetyl)-L-alaninyl)amino] 3-dihydro-l1-(2- N, N-diethyl aminoethyl)- 5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one '-(beta-phenyllactyl)-L-alaninyl)amino] 3-dihydro-l1-(2-N, Ndiethyl aminoethyl)- 5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2-one 3- -(mandelyl)-L-alaninyl)amino] -2 ,3-dihydro-l1-(2-N, N-diethyl aminoethyl)- 5-(2-pyridyl)- 1H-1 ,4-benzodiazepin-2-one 3- -(4-chloromandelyl)-L-alaninyl)amino]-2 ,3-dihydro-l1-(2-N .Ndiethyl aminoethyl)- 5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2-one 3- -(isovaleryl)-L-alaninyl)aniino] 3-dihydro-l1-(2-N ,N-diethyl aminoethyl)- 5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2-one ,5-trifluorophenylacetyl)-L-alaninyl)amino]-2 ,3-dihydro-l1-(2- N, N-diethyl aminoethyl)- 5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one '-(3-methylthiopropionyl)-L-alaninyl)amino]-2, 3-dihydro-l1-(2-N, Ndiethyl aminoethyl)- 5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2-one -(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino] 3-dihydro-l1-(2- N, N-diethyl aminoethyl)- 5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3- '-(3-nitrophenylacetyl)-L-alaninyl)amino] -2 ,3-dihydro-l1-(2-N, Ndiethyl aminoethyl)- 5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2 -one 3- '-(D-3-phenyllactyl)-L-alaninyl)amino] 3-dihydro-l1-(2-N, Ndiethyl aminoethyl)- 5-(2-pyridyl)-1H-1 ,4-benzodiazepin-2-one ,5-difluorophenylacetyl)-L-alaninyl] -amino-2 ,4-dioxo- 1, (2-methylpropyl)-2 5-tetrahydro- 1H- 3- ,5-difluorophenylacetyl)-L-alaninyl] -amino-2 ,4-dioxo- (methyl)-2 5-tetrahydro- 1H-i, 3- ,5-difluorophenylacetyl)-L-alaninyl] -amino-2 ,4-dioxo- (cyclopropylmethyl)-2.3 ,4,5-tetrahydro-l1H-i 3- ,5-difluorophenylacetyl)-L-vainyl -amino-2 ,4-dioxo- 1, (2-methylpropyl)-2 5-tetrahydro- 1H- WO 98/28268 PCT/US97/22986 56-- 3- ,5-difluorophenylacetyl)-L-valinyl] -amino-2 ,4-dioxo- 1, (methyl)-2 5-tetrahydro- 1H-i 3- ,5-difluorophenylacetyl)-L-valinylj -amino-2 ,4-dioxo- (cyclopropyimethyl)-2 5-tetrahydro- 1 H-i1, ,5-difluorophenylacetyl)-L-norvalinyl]-amino-2 ,4-dioxo- bis-(2-methylpropyl)-2 ,3,4 ,5-tetrahydro- 1 H-i 1, 3- ,5-difluorophenylacetyl)-L-norvalinyl] -amino-2 ,4-dioxo- bis-(methyl)-2 ,3 5-tetrahydro- 1 H-i1, ,5-difluorophenylacetyl)-L-norvalinyl] -amino-2 ,4-dioxo- bis-(cyclopropylmethyl)-2 5-tetrahydro- 1 H-i 3- ,5-difluorophenylacetyl)-L-methioninyl]-amino-2 ,4-dioxo- bis-(2-methylpropyl)-2 ,3 5-tetrahydro- 1 H-i 1, ,5-difluorophenylacetyl)-L-methioninyl] -amino-2 ,4-dioxo- bis-(methyl)-2.3 ,4,5-tetrahydro- 1 H-i1, ,5-difluorophenylacetyl)-L-methioninyl]-amino-2 ,4-dioxo- bis-(cyclopropylmethyl)-2, 3,4, 5-tetrahydro- 1 H-i 3- ,5-difluorophenylacetyl)-L-phenylalaninyl]-amino-2 ,4-dioxo- 1, 5-bis-(2-methylpropyl)-2 5-tetrahydro- 1H- 1, ,5-difluorophenylacetyl)-L-phenylalaninyl]-amino-2 ,4-dioxo- 1, 5-bis-(methyl)-2 5-tetrahydro-lH ,5-difluorophenylacetyl)-L-phenylalaninyl]-amino-2 ,4-dioxo- 1, 5-bis-(cyclopropylniethyl)-2 ,3,4 ,5-tetrahydro- 1 H-i ,5-difluorophenylacetyl)-L-phenylglycinyl]-amino-2 ,4-dioxo- 1 ,5-bis-(2-methylpropyl)-2 ,3 ,4 ,5-tetrahydro- 1 H-i ,5-difluorophenylacetyl)-L-phenylglycinyl]-amino-2 ,4-dioxo- 1, 5-bis-(methyl)-2, 3,4, 5-tetrahydro- iH- 1, 3- ,5-difluorophenylacetyl)-L-phenylglycinyl] -amino-2 ,4-dioxo- 1, 5-bis-(cyclopropylmethyl)-2 ,3 ,4,5-tetrahydro- 1H- 1 .5-difluorophenylacetyl)-(2-thienyl)glycine] -amino-2 ,4-dioxo- 1 ,5-bis-(2-methylpropyl)-2 ,3 5-tetrahydro- 1 H-i ,5-difluorophenylacetyl)-(2-thienyl)glycine]-amino-2 ,4-dioxo- 1 ,5-bis-(methyl)-2,3,4 ,5-tetrahydro- 1 H-i WO 98/28268 PCT[US97t22986 57 ,5-difluorophenylacetyl)-(2-thienyl)glycine] -amino-2 ,4-dioxo- 1 ,5-bis-(cyclopropylmethyl)-2.3 ,4,5-tetrahydro- 1H- 1, ,5-difluorophenylacetyl)-(3-thienyl)glycine] -amino-2 ,4-dioxo- 1, 5-bis-(2-methylpropyl)-2 5-tetrahydro- 1 H-1, ,5-difluorophenylacetyl)-(3-thienyl)glycine]-amino-2 ,4-dioxo- 1 ,5-bis-(methyl)-2 ,3 5-tetrahydro- 1 H-i1, ,5-difluorophenylacetyl)-(3-thienyl)glycine] -amino-2 ,4-dioxo- 1 ,5-bis-(cyclopropylmethyl)-2 ,3,4 ,5-tetrahydro- 1 H-i1, 3- ,5-difluorophenylacetyl)-L-threoninyll-amino-2 ,4-dioxo- bis-(2-methylpropyl)-2 ,3 ,4,5-tetrahydro- 1H-i ,5-difluorophenylacetyl)-L-threoninyl]-amino-2 ,4-dioxo- 1, 5-bis-(methyl)-2 ,3 ,4,5-tetrahydro- 1 H-i ,5-difluorophenylacetyl)-L-threoninyl]-amino-2 ,4-dioxo- bis-(cyclopropylmethyl)-2 ,3 ,4,5-tetrahydro- 1H- 1 ,5-difluorophenylacetyl)-L-tyrosinyll-amino-2 ,4-dioxo- 1 (2-methylpropyl)-2,3,4 ,5-tetrahydro- 1 H-i ,5-difluorophenylacetyl)-L-tyrosinylj -amino-2 ,4-dioxo- 1, (methyl)-2 ,3 ,4,5-tetrahydro- 1H- 1, ,5-difluorophenylacetyl)-L-tyrosinyl] -amino-2 ,4-dioxo- bis-(cyclopropylmethyl)-2.3 ,4,5-tetrahydro- 1 H-i 3-IIN-(cyclopentylacetyl)-L-alaninyl] -amino-2 ,4-dioxo- 1, (2-methylpropyl)-2 5-tetrahydro- 1 H-1, 3-[N-(cyclopentylacetyl)-L-alaninyl]-amino-2 ,4-dioxo- 1 (methyl)-2 ,3 ,4,5-tetrahydro- 1H- 1, 3-[N-(cyclopentylacetyl)-L-alaninyl]-amino-2 ,4-dioxo- (cyclopropylmethyl)-2 5-tetrahydro- 1 H-i 3-[N-(cyclopentylacetyl)-L-valinyl] -amino-2 ,4-dioxo- (2-methylpropyl)-2 5-tetrahydro- LH- 1 3- [N-(cyclopentylacetyl)-L-valinylj-amino-2 ,4-dioxo- (methyl)-2 5-tetrahydro- 1 H-i1, 3 -[N-(cyclopentylacetyl)-L-valinyl]-amino-2 ,4-dioxo- (cyclopropylmethyl)-2 5-tetrahydro- 1 H-i WO 98/28268 PCT1US97122986 58 3-[N-(cyclopentylacetyl)-L-norvalinyl] -amino-2 ,4-dioxo- bis-(2-methylpropyl)-2 5-tetrahydro- 1 H-i 3-[N-(cyclopentylacetyl)-L-norvalinyl]-amino-2 ,4-dioxo- bis-(methyl)-2,3,4, 5-tetrahydro- 1H- 1, 3-[N-(cyclopentylacetyl)-L-norvalinyl] -amino-2 ,4-dioxo- bis-(cyclopropylmethyl)-2, 3,4, 5-tetrahydro- 1H- 1 3-[N-(cyclopentylacetyl)-L-methioninyl] -amino-2 ,4-dioxo- bis-(2-methylpropyl)-2 ,3 ,4 ,5-tetrahydro- 1 H-i 3-[N-(cyclopentylacety1)-L-methioninyl]-amino-2 ,4-dioxo- bis-(methyl)-2 ,3 ,4,5-tetrahydro- 1 H-i1, 3-IIN-(cyclopentylacetyl)-L-methioninyl] -amino-2 ,4-dioxo- bis-(cyclopropylmethyl)-2 ,3,4 ,5-tetrahydro- 1H- 1, 3-[N-(cyclopentylacetyl)-L-phenylalaninyl] -amino-2 ,4-dioxo- 1, 5-bis-(2-methylpropyl)-2, 3,4,5-tetrahydro- 1 H-i1, 3-[N-(cyclopentylacetyl)-L-phenylalaninyl]-amino-2 ,4-dioxo- 1, 5-bis-(methyl)-2 5-tetrahydro- 1 H-1, 3-[N-(cyclopentylacetyl)-L-phenylalaninyl]-amino-2 ,4-dioxo- 1, 5-bis-(cyclopropylmethyl)-2.3 ,4,5-tetrahydro-l1H-i 3-IIN-(cyclopentylacetyl)-L-phenylglycinyll-amino-2 ,4-dioxo- 1, 5-bis-(2-methylpropyl)-2 5-tetrahydro- 1 H-i1, 3-[N-(cyclopentylacetyl)-L-phenylglycinyl]-amino-2 ,4-dioxo- 1 ,5-bis-(methyl)-2,3 ,4,5-tetrahydro-iH- 1 3-[N-(cyclopentylacetyl)-L-phenylglycinyl]-amino-2 ,4-dioxo- 1 ,5-bis-(cyclopropylmethyl)-2 5-tetrahydro- 1 H-i 3-IIN-(cyclopentylacetyl)-(2-thienyl)glycine]-amino-2 ,4-dioxo- 1 ,5-bis-(2-methylpropyl)-2 5-tetrahydro- 1 H-i, 3-[N-(cyclopentylacetyl)-(2-thienyl)glycine]-amino-2 ,4-dioxo- 1, 5-bis-(methyl)-2 5-tetrahydro-l1H-i 3-[N-(cyclopentylacetyl)-(2-thienyl)glycine] -amino-2 ,4-dioxo- 1, 5-bis-(cyclopropylmethyl)-2 5-tetrahydro- 1 H-i 3-IIN-(cyclopentylacetyI)-(3-thieny1)glycine]-amino-2 ,4-dioxo- 1 ,5-bis-(2-methylpropyl)-2 5-tetrahydro- 1 H-i, WO 98/28268 PCTIUS97/22986 59 3-[N-(cyclopentylacetyl)-(3-thienyl)glycine] -amino-2 ,4-dioxo- 1, 5-bis-(methyl)-2, 3,4 ,5-tetrahydro- 1 H- 1,5 -benzodiazepine 3-[N-(cyclopentylacetyl)-(3-thienyl)glycine] -amino-2 .4-dioxo- 1, 5-bis-(cyclopropylmethyl)-2 ,3,4 ,5-tetrahydro- 1H- 1 3 -[N-(cyclopentylacetyl)-L-serinyl]-ainino-2 ,4-dioxo- 1, (2-methylpropyl)-2.3 ,4,5-tetrahydro- 11- 1, 3- [N-(cyclopentylacetyl)-L-threoninyl] -amino-2 ,4-dioxo- bis-(2-methylpropyl)-2 ,3 ,4,5-tetrahydro- 1 H-i 3-[N-(cyclopentylacetyl)-L-threoninyl]-amino-2,4-dioxo- bis-(methyl)-2 ,3 ,4,5-tetrahydro- 1 H-i 3- [N-(cyclopentylacetyl)-L-threoninyl] -amino-2 ,4-dioxo- bis-(cyclopropylmethyl)-2 ,3,4 ,5-tetrahydro- 1 H-i 3-[N-(cyclopentylacetyl)-L-tyrosinyl] -amino-2 ,4-dioxo- (2-methylpropyl)-2 5-tetrahydro- 1H-i 3-[N-(cyclopentylacetyl)-L-tyrosinyl] -amino-2 ,4-dioxo- bis-(methyl)-2,3,4, 5-tetrahydro- 1 H-i 3-[N-(cyclopentylacetyl)-L-tyrosinyl]-amino-2 ,4-dioxo- bis-(cyclopropylmethyl)-2 ,3 ,4,5-tetrahydro- 1 H-i ,4 ,4-trifluorobutryl)-L-alaninyl]-amino-2 ,4-dioxo- (2-methylpropyl)-2 5-tetrahydro- 1H- 1, 3-[N-(4,4,4-trifluorobutryl)-L-alaninyl]-amino-2 ,4-dioxo- bis-(methyl)-2 ,3,4 ,5-tetrahydro- 1 H-i 3-IIN-(4,4,4-t 'rifluorobutryl)-L-alaninyl] -amino-2 ,4-dioxo- (cyclopropylmethyl)-2 5-tetrahydro- 1 H-i 3- ,4 ,4-trifluorobutryl)-L-valinyl]-amino-2 ,4-dioxo- (2-methylpropyl)-2 ,3,4 ,5-tetrahydro-IH ,4,4-trifluorobutryl)-L-valinyl] -amino-2 ,4-dioxo-l1,5-bis- -(methyl)-2 ,3,4 ,5-tetrahydro- iH- 3-IIN-(4,4,4-trifluorobutry)-L-valiny1l-amino-2 ,4-dioxo-1, (cyclopropylmethyl)-2 ,3,4 ,5-tetrahydro- 1 H-i ,4,4-trifluorobutryl)-L-norvalinyl]-amino-2 ,4-dioxo- bis-(2-methylpropyl)-2 ,3,4 ,5-tetrahydro- 1H-i WO 98/28268 PCT/US97/22986 60 ,4-trifluorobutryl)-L-norvalinylJ -amino-2 ,4-dioxo- bis-(methyl)-2 5-tetrahydro- 1 H-i ,4-trifluorobutryl)-L-norvalinyl] -amino-2 ,4-dioxo- bis-(cyclopropylmethyl)-2 ,3 ,4,5-tetrahydro-l1H-I 3-[N-(4,4,4-trifluorobutryl)-L-methioninyl] -amino-2 ,4-dioxo- bis-(2-methylpropyl)-2, 3,4 ,5-tetrahydro- 1 H-i1, ,4-trifluorobutryl)-L-methioninyl]-amino-2 ,4-dioxo- bis-(methyl)-2 5-tetrahydro- 1 H-i ,4-trifluorobutryl)-L-methioninyl]-amino-2 ,4-dioxo- bis-(cyclopropylmethyl)-2 5-tetrahydro- 1 H-i1, 3- [N-(4,4,4-trifluorobutryl)-L-phenylalaninyl]-amino-2 ,4-dioxo- 1, 5-bis-(2-methylpropyl)-2 ,3 5-tetrahydro- 1H- 3- ,4-trifluorobutryl)-L-phenylalaninyl]-amino-2 ,4-dioxo- 1, 5-bis-(methyl)-2 ,3 ,4,5-tetrahydro- 1 H-i1, ,4 ,4-trifluorobutryl)-L-phenylalaninyl-amino-2 ,4-dioxo- 1, 5-bis-(cyclopropylmethyl)-2 ,3,4 ,5-tetrahydro- 1H- 1, ,4-trifluorobutryl)-phenylglycinyl]-amino-2 ,4-dioxo- 1,5-bis-(2-methylpropyl)-2, 3,4, 5-tetrahydro- 1H- 1, 3-IiN-(4,4,4-trifluorobutryl)-L-phenylglycinyl] -amino-2 ,4-dioxo- 1 ,5-bis-(methyl)-2, 3,4,5-tetrahydro-l1H-i 3- [N-(4,4,4-trifluorobutryl)-L-(2-thienyl)glycine-aynino-2 ,4dioxo- 1 ,5-bis-(2-methylpropyl)-2,3 ,4,5-tetrahydro- 1H- 1, 3-[N-(4,4,4-trifluorobutryl)-L-(2-thienyl)glycine]-amino-2 ,4dioxo- 1,5-bis-(methyl)-2 ,3,4 ,5-tetrahydro-l1H-i ,4 ,4-trifluorobutryl)-L-(2-thienyl)glycine] -amino-2 ,4dioxo- 1 ,5-bis-(cyclopropylmethyl)-2 ,3 ,4,5-tetrahydro- 1 H-1, benzodiazepine ,4 ,4-trifluorobutryl)-L-(3-thienyl)glycine]-amino-2 ,4dioxo- 1 ,5-bis-(2-methylpropyl)-2,3,4, 5-tetrahydro- 1 H-i1, 3-[N-(4,4,4-trifluorobutry)-L-(3-thieny)gycinel-amino-2 ,4dioxo- 1 ,5-bis-(methyl)-2 ,3,4 ,5-tetrahydro- 1H- 1 WO 98/826 PCTIUS97/22986 61 ,4,4-trifluorobutryl)-L-(3-thienyl)glycine-amino-2 ,4dioxo- 1,5-bis-(cyclopropylmethyl)-2 ,3 ,4,5-tetrahydro-l1H- -benzodiazepine ,4 ,4-trifluorobutryl)-L-cyclohexylglycinyl] -amino-2 ,4dioxo- 1 ,5-bis-(2-methylpropyl)-2 ,3 5-tetrahydro- 1 H-i1, 3-[N-(4,4,4-trifluorobutryl)-L-cyclohexylglycinyl] -amino-2 ,4- -dioxo- 1 ,5-bis-(methyl)-2 ,3 5-tetrahydro- 1H- 1 3-[N-(4,4,4-trifluorobutryl)-L-cyclohexylglycinyl] -amino-2 ,4dioxo- 1 ,5-bis-(cyclopropylmethyl)-2.3 ,4,5-tetrahydro- 111-1,5benzodiazepine ,4-trifluorobutryl)-L-threoninyl] -amino-2 ,4-dioxo- bis-(2-methylpropyl)-2.3 ,4,5-tetrahydro- 1 H-i ,4,4-trifluorobutryl)-threoninylJ -amino-2 ,4-dioxo- bis-(methyl)-2 ,3,4 ,5-tetrahydro- 1 H-i 3-[N-(4,4,4-trifluorobutryl)-L-threoninyl] -amino-2 ,4-dioxo- bis-(cyclopropylmethyl)-2 ,3 ,4 ,5-tetrahydro- 1 H-i1, 3-(3 ,5-difluorophenylacetyl)amino-2 ,3-dihydro-l1-methyl-5-phenyl- lH- 1 ,4-benzodiazepin-2-one 3-(N ,5-difluorophenylacetyl)-L-alaninyl)amino-2 ,3-dihydro-l1-ethyl-5phenyl- 1H- 1,4-benzodiazepin-2-one 3-[N ,5-difluorophenylacetyl)-L-alaninyl]-amino-2 11- 1 ,4-benzodiazepin-2-one 3-[N ,5-difluorophenylacetyl)-L-alaninyl] -amino-2 ,3-dihydro- 1- 1-piperidinyl)- 11-1 ,4-benzodiazepin-2-one 3-[N ,5-difluorophenylacetyl)-L-alaninyl]-amino-7-chloro-2 ,3-dihydro- 1 -methyl-5-phenyl-l11-1 ,4-benzodiazepin-2-one 3-[N ,5-difluorophenylacetyl)-L-alaninyl] -amino-7-bromo-2 ,3-dihydro- 1-methyl-5-(2-fluorophenyl)-1H-1 ,4-benzodiazepin-2-one 3 ,5-difluorophenylacetyl)-N' -methyl-L-alaninyl] -amino-2 .3dihydro-1 -methyl-5-phenyl-1H- 1,4-benzodiazepin-2-one 3-[N ,5-difluorophenylacetyl)-L-alaninyl] -amino-7-chloro-2 ,3-dihydro- 1 -methyl-5-(2-chloropheny 1)-iH-i ,4-benzodiazepin-2-one WO 98/8268 PCT/US97t22986 62-- 3-[N ,5-difluorophenylacetyl)-L-alaninyl] -amino-S -cyclohexyl-2 ,3dihydro- 1-methyl- 1H-1 ,4-benzodiazepin-2-one 3-[N ,5-difluorophenylacetyl)-L-alaninyl]-amino-2, 3-dihydro- 1 methyl-7-nitro-5-phenyl-l1H-i ,4-benzodiazepin-2-one ,5-difluorophenylacetyl)-L-alaninyll-amino-2 ,3-dihydro- 1methyl-5-(2-fluorophenyl)- 1H- 1 ,4-benzodiazepin-2-one 3- ,5-difluorophenyl-ca-hydroxyacetyl)-L-valinylj-amino-2 ,3dihydro-1 -methyl-5-phenyl- 111- 1,4-benzodiazepin-2-one ,5-difluorophenyl-ce-hydroxyacetyI)-L-tert-leucinyl] -amino-2, 3dihydro- 1 -methyl-5-phenyl- 1H- 1, 4-benzodiazepin-2-one 3-[N ,5-difluorophenylacetyl)-L-alaninyl] -amino-2 ,3-dihydro- 1methyl-5-(3-fluorophenyl)- 1H- 1,4-benzodiazepin-2-one 3-[N ,5-difluorophenylacetyl)-L-alaninyllamino-2 ,3-dihydro- I1-methyl- 5-(4-fluorophenyl)- lH- 1,4-benzodiazepin-2-one 3-[N '-(cyclopentyl-ca-hydroxyacetyl)-L-alaninyl]-amino-2, 3-dihydro- 1- 1H- 1,4-benzodiazepin-2-one 3-[N '-(cyclopentyl-cr-hydroxyacetyl)-L-valinyl]-amino-2 ,3-dihydro- 1methyl-5-phenyl-l1H-i ,4-benzodiazepin-2-one 3-[N ,5-difluorophenylacetyl)-L-alaninyl]amino-2, 3-dihydro- dimethyl-l1H-i ,4-benzodiazepin-2-one 3-[N ,5-difluorophenylacetyl)-L-alaninyljamino-2 ,3-dihydro- 1 lH- 1,4-benzodiazepin-2-one 3-[N 5-difluorophenyl-ca-hydroxyacetyl)-L-alaninyllamino-2 ,3dihydro- 1-methyl-5-phenyl-l11-1 ,4-benzodiazepin-2-one 3-[N ,5-difluorophenyl-a-oxoacetyl)-L-alaninyllamino-2 ,3-dihydro- 1methyl-5-phenyl-1H- 1,4-benzodiazepin-2-one -(2-methylthioacetyl)-L-alaninyllamino-2 ,3-dihydro-l1-methyl-5phenyl- 11-1 ,4-benzodiazepin-2-one 3-[N ,5-difluorophenylacetyl)-L-valinyl] amino-2 ,3-dihydro- 1-methyl- ILH- 1 ,4-benzodiazepin-2-one 3-[N ,5-difluorophenylacetyl)-L-tert-leuciny1]amino-2 ,3-dihydro- 1 methyl-5-phenyl-l1H-i ,4-benzodiazepin-2-one WO W828268 PCT1US97122986 63 3-[N ,5-difluorophenylacetyl)-L-alaninyl]amino-2 ,3-dihydro- 1- 1 H-i ,4-benzodiazepin-2-one 3-[N ,5-difluorophenylacetyl)-L-alaninyl]amino-2 ,3-dihydro- 1cyclopropylmethyl-5-phenyl-1H-1 ,4-benzodiazepin-2-one 3-[N 5-difluoropheny1-ci-fluoroacety1)-L-alaniny1]amino-2 ,3-dihydro- 1H- 1,4-benzodiazepin-2-one 3- 5-difluorophenylacetyl)-L-alaninyllaniino-2 ,3-dihydro- 1-n- 1H- 1 ,4-benzodiazepin-2-one 3-[N '-(3-methylbutyryl)-L-phenylglycinyl]amino-2 ,3-dihydro-l1-methyl-5phenyl- 1H- 1,4-benzodiazepin-2-one 3- ,5-difluorophenylacetyl)-L-phenylglycinyl] amino-2, 3-dihydro- 1 methyl-5-phenyl-l1H-i ,4-benzodiazepin-2-one 3-[N '-(2-phenyhthioacetyl)-L-alaninyllamino-2 ,3-dihydro-l1-methyl-5phenyl- 1H- 1,4-benzodiazepin-2-one 3-[N '-(3-methylbutyryl)-L-alaninyllamino-2 ,3-dihydro- 1 phenyl- 1H-i ,4-benzodiazepin-2-one 3- -(2-phenylthioacetyl)-L-phenylglycinyl~amino-2, 3-dihydro- 1 -methyl- 1H- 1,4-benzodiazepin-2-one 3-[N '-(3-(4-methoxyphenyljpropionyl)-L-alaninyljamino-2 ,3-dihydro- 1- 1H- 1,4-benzodiazepin-2-one -(3-bromophenylacetyl)-L-alaninyl]amino-2 ,3-dihydro-l1-methyl-5phenyl- 1H-1 ,4-benzodiazepin-2-one 3-[N '-(4-cyclohexylbutyryl)-L-alaninyl] amino-2 ,3-dihydro-l1-methyl-5phenyl-1H-1 ,4-benzodiazepin-2-one 3-[N '-(4-methoxyphenylacetyl)-L-alaninyllamino-2 ,3-dihydro- (2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3-[N '-(3-methyl-2-hydroxylbutyryl)-L-alaninyllamino-2 ,3-dihydro- 1- 1 H-i ,4-benzodiazepin-2-one 3-[N '-(3-methyl-2-hydroxylbutyryl)-L-alaninyllamino-2, 3-dihydro- 1 lH- 1,4-benzodiazepin-2-one 3-[N 3-dimethylbutyryl)-L-alaninyl] amino-2 ,3-dihydro- phenyl-l1H-i ,4-benzodiazepin-2-one WO 98/28268 PCT11JS97/22986 64 3-[N '-(thien-2-yl-acetyl)-L-alaninylj amino-2 ,3-dihydro- 1 -methyl-5-(2pyridyl)- 1i,4-benzodiazepin-2-one 3-[N ,5-difluorophenylacetyl)-L-alaninyl]amino-2 ,3-dihydro-l1-methyl- 5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3-[N '-(3-bromophenylacetyl)-L-alaninyl]amino-2 ,3-dihydro-l1-methyl-5- (2-pyridy H- 1,4-benzodiazepin-2-one -(2-phenylthioacetyl)-L-alaninyljamino-2, 3-dihydro- 1 -methyl-5-(2pyridyl)- 1 H-i ,4-benzodiazepin-2-one 3- [N'-(4-ethoxyphenylacetyl)-L-alaninyl] amino-2 ,3-dihydro-l1-methyl-5- (2-pyridyl)- 1 H-i ,4-benzodiazepin-2-one 3-[N '-(4-trifluoromethylphenylacetyl)-L-alaninyljamino-2 ,3-dihydro- 1 methyl-5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2-one 5-di(trifluoromethyl)phenylacetyl)-L-alaninyl]amino-2 ,3dihydro- 1 -methyl-5-(2-pyridyl)- 1 H-i ,4-benzodiazepin-2-one 3- [N '-(2-methylthioacetyl)-L-alaninyllamino-2 ,3-dihydro- 1 -methyl-5-(2pyridyl)- lH- 1,4-benzodiazepin-2-one 3-[N '-(2-cyclohexylacetyl)-L-alaninyl]amino-2 ,3-dihydro-l1-methyl-5-(2pyridyl)-l1H-i ,4-benzodiazepin-2-one 3-[N ,6-pentafluorophenoxyacetyl)-L-alaninyljamino-2, 3dihydro- 1 -methyl-5-(2-pyridyl)- 1 H-i ,4-benzodiazepin-2-one 3- -(thionaphth-3-ylacetyl)-L-alaninyl]amino-2 ,3-dihydro- 1 (2-pyridyl)- 1H-i ,4-benzodiazepin-2-one 3-[N 6-trimethylphenylacetyl)-L-aianinyl]amino-2 ,3-dihydro- I1methyl-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3- -((4-phenyl)phenylacetyl)-L-alaninyl]amino-2 ,3-dihydro- 1 (2-pyridyl)- 1H-i ,4-benzodiazepin-2-one 3-[N ,4-difluorophenylacetyl)-L-alaninyllamino-2 ,3-dihydro- i-methyl- 5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3- -(4-(thien-2-yl)butyryl)-L-alaninyl]amino-2 ,3-dihydro- 1 (2-pyridyl)-1H- 1,4-benzodiazepin-2-one 3-[N '-(5-methylhexanoyl)-L-alaninyl] amino-2 ,3-dihydro- 1 -methyl-5-(2pyridyl)- 1H- 1,4-benzodiazepin-2-one WO 98/28268 PCT[US97/22986 3-[N '-(2-methoxycarbonylacetyl)-L-alaninyl] amino-2 ,3-dihydro-l1-methyl- 5-(2-pyridyl)-1H- 1,4-benzodiazepin-2-one 3-[N ,6-difluorophenyl)-a-hydroxyacetyl)-L-alaninyl]amino-2 ,3dihydro- 1 -methyl-5-(2-pyridyl)- 1 H-i ,4-benzodiazepin-2-one 3-[N '-(4-fluorophenyl)-ae-hydroxyacetyl)-L-alaninyl] amino-2 ,3-dihydro- 1methyl-5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2-one 3-[N ,5-difluorophenyl)-ca-hydroxyacetyl)-L-alaninylj amino-2 ,3dihydro- 1-methyl-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3- 6-trifluorophenyl)acetyl)-L-alaninyljamino-2 ,3-dihydro- 1methyl-5-(2-pyridyl)- 1H- 1 ,4-benzodiazepin-2-one 3- -(2-trifluoromethyl-4-fluorophenyl)acetyl)-L-alaninyl]amino-2 ,3dihydro- 1 -methyl-5-(2-pyridyl)- 1 H-i ,4-benzodiazepin-2-one 3-[N ,4,4-trifluorobutyryl)-L-alaninyl] amino-2 ,3-dihydro-l1-methyl-5- (2-pyridy 1H- 1,4-benzodiazepin-2-one 3- [N '-(4-iso-propylphenylacetyl)-L-alaninyl] amino-2 ,3-dihydro- 1-methyl- 5-(2-pyridyl)- lH- 1,4-benzodiazepin-2-one 3- [N '-(3-phenyl-2-hydroxypropionyl)-L-alaninyllamino-2 ,3-dihydro- 1methyl-5-(2-pyridyl)- 1H- 1,4-benzodiazepin-2-one 3-[N '-(phenyl-ca-hydroxyacetyl)-L-alaninyl] amino-2 ,3-dihydro- 1-methyl- 5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2-one 3-[N '-(4-chlorophenyl-ca-hydroxyacetyl)-L-alaninyl]amino-2 ,3-dihydro- 1 methyl-5-(2-pyridyl)- 1H- 1,4-benzodiazepin-2-one 3-[N '-(3-methylbutyryl)-L-alaninyl] amino-2 ,3-dihydro-l1-methyl-5-(2pyridyl)-l1H-i ,4-benzodiazepin-2-one 3-[N 5-trifluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro- 1methyl-5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2-one 3-[N '-(3-methylthiopropionyl)-L-alaninyl] amino-2,3-dihydro-l1-methyl-5- (2-pyridyl)- iH- 1,4-benzodiazepin-2-one 3- [N '-(3-methyl-2-hydroxybutyryl)-L-alaninyl]amino-2 ,3-dihydro- 1methyl-5-(2-pyridyl)-i1H-i ,4-benzodiazepin-2-one 3-[N '-(3-nitrophenylacetyl)-L-alaninylj aiino-2 ,3-dihydro-l1-methyl-5-(2pyridyl)- 1 H-i ,4-benzodiazepin-2-one WO 98/28268 PCT/US97122986 66 3-[N '-(4-methoxyphenylacetyl)-L-alaninyllamino-2 ,3-dihydro-l1-(tertbutylcarbonylmethyl)-5-(2-pyridyl)- 1H- 1 4 -benzodiazepin-2-one 3- [N'-(2-thienylacetyl)-L-alaninyljaniino-2 ,3-dihydro- 1-(tertbutylcarbonylmethyl)-5-(2-pyridyl)- 1HW 1 ,4-benzodiazepin-2-one 3-[N ,5-difluorophenylacetyl)-L-alaninyl] amino-2 ,3-dihydro- 1-(tertbutylcarbonylmethyl)-5-(2-pyridyl)- 1 H-i ,4-benzodiazepin-2-one 3- -(3-bromophenylacetyl)-L-alaninyllamino-2 ,3-dihydro-l1-(tertbutylcarbonylmethyl)-5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2-one 3-[N '-(2-phenylthioacetyl)-L-alaninyllamino-2 ,3-dihydro- 1 -(tertbutylcarbonylmethyl)-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3- -(4-ethoxyphenylacetyl)-L-alaninyl] amino-2 ,3-dihydro- 1 -(tertbutylcarbonylmethyl)-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3-IN' -(4-trifluoromethylphenylacetyl)-L-alaninyl]amino-2 ,3-dihydro- 1- (tert-butylcarbonylmethyl)-5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2-one 3-[N 5-di-(trifluoromethyl)phenylacetyl)-L-alaninyljanino-2 .3dihydro-l1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-l1H-i ,4-benzodiazepin- 2-one 3-[N '-(2-methylthioacetyl)-L-alaninyllamino-2 ,3-dihydro-l1-(tenTbutylcarbonylmethyl)-5-(2-pyridyl)- 1 H-i ,4-benzodiazepin-2-one 3- -(2-cyclomethylacetyl)-L-alaninyl] amino-2,3-dihydro- 1 -(tellbutylcarbonylmethyl)-5-(2-pyridyl)- 1 H-i ,4-benzodiazepin-2-one 3-[N ,6-pentafluorophenoxyacetyl)-L-alaninyl] amino-2,3dihydro- i-(tert-butylcarbonylmethyl)-5-(2-pyridyl)- 1H-i, 4-benzodiazepin- 2-one 3- [N '-(thionaphth-3-ylacetyl)-L-alaninyl]amino-2 ,3-dihydro-l1-(tentbutylcarbonylmethyl)-5-(2-pyridyl)- 1H- 1 ,4-benzodiazepin-2-one 3- 6-trimethylphenylacetyl)-L-alaninyl]amino-2 3-dihydro- 1 -(tellbutylcarbonylmethyl)-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3-[N '-((4-phenyl)phenylacetyl)-L-alaninyllamino-2,3-dihydro-l1-(tentbutylcarbonylmethyl)-5-(2-pyridyl)-l1H-i, 4-benzodiazepin-2-one 3-[N ,4-difluorophenylacetyl)-L-alaninyl] amino-2,3-dihydro-l1-(tentbutylcarbonylmethyl)-5-(2-pyridyl)- 1H- 1,4-benzodiazepin-2-one WO 98/28268 PCTfUS97I22986 67-- 3-[N '-(4-(2-thienyl)butyryl)-L-alaninyl]amino-2 ,3-dihydro-l1-(tertbutylcarbonylmethyl)-5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2-one 3-[N '-(5-methylhexanoyl)-L-alaninyl]amino-2 ,3-dihydro-l1-(tertbutylcarbonylmethyl)-5-(2-pyridyl)- 1H- 1, 4-benzodiazepin-2-one 3-[N '-(2-methoxycarbonylacetyl)-L-alaninyllamino-2 ,3-dihydro-l1-(tertbutylcarbonylmethyl)-5-(2-pyridyl)-l- 11,4-benzodiazepin-2-one 3-[N ,6-difluoropheny-a-hydroxyacety)-L-alaniny~amino-2 ,3dihydro-l1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-l1H-i ,4-benzodiazepin- 2-one 3-[N '-(4-fluorophenyl-ca-hydroxyacetyl)-L-alaninyl]amino-2 ,3-dihydro- 1- (tert-butylcarbonylmethyl)-5-(2-pyridyl)- lH- 1,4-benzodiazepin-2-one 3-[N ,5-difluorophenyl-ca-hydroxyacetyl)-L-alaninyl]amino-2 ,3dihydro-l1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-l1H-i ,4-benzodiazepin- 2-one 3-[N 6-trifluorophenylacety1)-L-alaniny~amino-2 ,3-dihydro- 1 -(terlbutylcarbonylmethyl)-5-(2-pyridyl)- 1 H-i ,4-benzodiazepin-2-one 3-[N '-(2-trifluoromethyl-4-fluorophenylacetyl)-L-alaniny]amino.2 3dihydro-l1-(terT-butylcarbonylmethyl)-5-(2-pyridyl)-l1H-i, 4-benzodiazepin- 2-one 3-[N ,4-trifluorobutyryl)-L-alaninyljamino-2 ,3-dihydro-l1-(tertbutylcarbonylmethyl)-5-(2-pyridyl)- 1H- 1,4-benzodiazepin-2-one 3-[N '-(4-iso-propylphenylacetyl)-L-alaninyl]amino-2 ,3-dihydro-l1-(tertbutylcarbonylmethyl)-5-(2-pyridyl)- 1 H-i ,4-benzodiazepin-2-one 3-[N '-(3-phenyl-2-hydroxypropionyl)-L-alaninyl]amino-2 ,3-dihydro- 1- (tert-butylcarbonylmethyl)-5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2-one 3-[N '-(pheny1-ci-hydroxyacetyl)-L-alaninyl]amino-2 3-dihydro- 1 -(tertbutylcarbonylmethyl)-5-(2-pyridyl)- 1H- 1 ,4-benzodiazepin-2-one 3-[N '-(4-chlorophenylacetyl)-L-alaninyl] arnino-2,3-dihydro- 1 -(tertbutylcarbonylmethyl)-5-(2-pyridyl)- 1H- 1,4-benzodiazepin-2-one 3-[N '-(3-methylbutyryl)-L-alaninyllamino-2 ,3-dihydro-l1-(tertbutylcarbonylmethyl)-5-(2-pyridyl)- 1 H-i1, 4-benzodiazepin-2-one WO 98/28268 PCT/US97/22986 68-- 3-[N 5-trifluorophenylacetyl)-L-alaninyljamino-2 ,3-dihydro- 1 -(tertbutylcarbonylmethyl)-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3-[N '-(3-methylthiopropionyl)-L-alaninyl]amino-2, 3-dihydro- 1 -(tet-, butylcarbonylmethyl)-5-(2-pyridy1)-i 1H-i ,4-benzodiazepin-2-one 3-[N '-(3-methyl-2-hydroxybutyryl)-L-alaninyllamino-2 ,3-dihydro- 1 -(tertbutylcarbonylmethyl)-5-(2-pyridyl)- 1 H-i ,4-benzodiazepin-2-one 3-[N '-(3-nitrophenylacetyl)-L-alaninyljamino-2 ,3-dihydro- 1 -(tertbutylcarbonylmethyl)-5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2-one 3- [N'-(4-methoxyphenylacetyl)-L-alaninyl]amino-2 ,3-dihydro-l1-(2-(N ,Ndiethylamino)ethyl)-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3-[N '-(2-thienylacetyl)-L-alaninyl]amino-2 ,3-dihydro-l1-(2-(N ,Ndiethylamino)ethyl)-5-(2-pyridyl)- iH- 1,4-benzodiazepin-2-one ,5-difluorophenylacetyl)-L-alaninyllamino-2 ,3-dihydro-l1-(2- (N,N-diethylamino)ethyl)-5-(2-pyridyl)-iH-i ,4-benzodiazepin-2-one 3-[N '-(3-bromophenylacetyl)-L-alaninyl] amino-2 ,3-dihydro-l1-(2-(N, Ndiethylamino)ethyl)-5-(2-pyridyl)- 1H- 1 ,4-benzodiazepin-2-one 3-[N'-(2-phenylthioacetyl)-L-alaninyl]amino-2 ,3-dihydro-l1-(2-(N ,Ndiethylamino)ethyl)-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3-[N '-(4-ethoxyphenylacetyl)-L-alaninyl] amino-2 ,3-dihydro- 1 Ndiethylamino)ethyl)-5-(2-pyridyl)- 1 H-i1, 4-benzodiazepin-2-one 3-[N '-(2-methylthioacetyl)-L-alaninyllamino-2 ,3-dihydro-l1-(2-(N ,Ndiethylamino)ethyl)-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3-[N '-(2-cyclohexylacetyl)-L-alaninyl]amino-2 ,3-dihydro- 1 Ndiethylamino)ethyl)-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3- N ,6-pentafluorophenoxyacetyl)-L-alaninyl]amino-2 .3dihydro-l1-(2-(N ,N-diethylamino)ethyl)-5-(2-pyridyl)- 1H- 1,4benzodiazepin-2-one 3-IN' -(2-thionaphth-3-ylacetyl)-L-alaninyl] amino-2 ,3-dihydro-l1-(2-(N ,Ndiethylamino)ethyl)-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3-[N '-(2-phenyl-2-oxoacetyl)-L-alaninyl]amino-2 ,3-dihydro-l1-(2-(N ,Ndiethylamino)ethyl)-5-(2-pyridyl)- 1H-1 ,4-benzodiazepin-2-one 3-[N ,4,6-trimethylphenylacetyl)-L-alaninyllamino-2 ,3-dihydro-l1-(2- N-diethylamino)ethyl)-5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2-one WO 9=/8268 PCT/US97/22986 69 3-[N '-((4-phenyl)phenylacetyl)-L-alaninylJ amino-2 ,3-dihydro- 1 Ndiethylaxnino)ethyl)-5-(2-pyridyl)- 1H- 1, 4 -benzodiazepin-2-one 3- ,4-difluorophenyl)acetyl)-L-alaninyllamino-2 ,3-dihydro- 1 N-diethylamino)ethyl)-5-(2-pyridyl)- 1 H-i ,4-benzodiazepin-2-one 3-[N '-((4-(thien-2-yl)butyryl)-L-alaninyllamino-2 ,3-dihydro- 1 diethylamino)ethyl)-5-(2-pyridyl)- 1H- 1 ,4-benzodiazepin-2-one 3-[N '-(5-methylhexanoyl)-L-alaninyllamino-2 ,3-dihydro-l1-(2-(N ,Ndiethylamino)ethyl)-5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2-one 3- -(2-methoxycarbonylacetyl)-L-alaninyllamino.2 3-dihydro-l1-(2- N-diethylamino)ethyl)-5-(2-pyridyl)- 1 H-i ,4-benzodiazepin-2-one 3-[N 6-difluorophenyl-ca-hydroxyacetyl)-L-alaninyl]amino-2 3dihydro-l1-(2-(N ,N-diethylamino)ethyl)-5-(2-pyridyl)-l11-1,4benzodiazepin-2-one 3-[N '-(4-fluorophenyl-ca-hydroxyacetyl)-L-alaninyl] amino-2 ,3-dihydro- 1- ,N-diethylamino)ethyl)-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3-[N ,5-difluorophenyl-ca-hydroxyacetyl)-L-alaninyl] amino-2 ,3dihydro-l1-(2-(N ,N-diethylamino)ethyl)-5-(2-pyridyl)-l1H-i ,4benzodiazepin-2-one 3-[N '-(4-hydroxymethylphenoxyacetyl)-L-alaninylamino.2 3-dihydro- 1- (2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2-one ,4 ,6-trifluorophenylacetyl)-L-alaninyl] amino-2 ,3-dihydro- 1 N-diethylamino)ethyl)-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3 -[N'-(2-trifluoromethyl-4-fluorophenylacetyl)-L-alaninyl~amino-2 ,3dihydro- N-diethylamino)ethyl)-5-(2-pyridyl)-l11-1,4benzodiazepin-2-one 3-[N ,4,4-trifluorobutyryl)-L-alaninyl] amino-2, 3-dihydro- 1 Ndiethylamino)ethyl)-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3- -(4-iso-propylphenylacetyl)-L-alaninyl] amino-2 ,3-dihydro-l1-(2- (N,N-diethylamino)ethyl)-5-(2-pyridyl)-i1H- 1 ,4-benzodiazepin-2-one 3-[N '-(3-phenyl-2-hydroxypropionyl)-L-alaninyl] amino-2 ,3-dihydro- 1 N-diethylamino)ethyl)-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3-[N '-(phenyl-ca-hydroxyacetyl)-L-alaninyl]amino-2 ,3-dihydro-l1-(2-(N ,Ndiethylamino)ethyl)-5-(2-pyridyl)- 1H- 1 ,4-benzodiazepin-2-one WO 98/28268 PCT1US97/22986 3-[N '-(4-chloropheny1-a-hydroxyacety)-L-alaninylamino-2 ,3-dihydro- 1- N-diethylamino)ethyl)-5-(2-pyridyl)- 1 H-i ,4-benzodiazepin-2-one 3 5-difluoropheny-ci-hydroxyacety)-L-3-thienylglycinyI] amino- 2 ,4-dioxo- 1,5-bis(2 ,2-dimnethylpropyl)-2 ,3,4 ,5-tetrahydro- 1 H- benzodiazepine 3-[N ,5-difluorophenyl-ce-hydroxyacetyI)-L-alaniny1]amino-2 ,4-dioxo- 1 -phenyl-5-methyl-2 5-tetrahydro- 1H- 1 3- 5-difluorophenyl-a-hydroxyacetyl)-L-alaninyl]amino-2-oxo 1- 1,3 ,4,5-tetrahydro- 1H- 1 3- ,5-difluorophenylacetyl)-L-alaninyl]aniini-L- 1H-imidazole[ 1,2-a] 6-phenyl-1 ,4-benzodiazepine 4-[N ,5-difluorophenylacetyl)-L-alaninyl] amino-L- 1H-imidazole[ 1,2a]-2 ,4-dihydro-6-phenyl- 1,4-benzodiazepine 4-[N 4H[ 1,2 ,4]triazole[4 ,3-a]-6-phenyl- 1,4-benzodiazepine 3-[N ,5-difluorophenylacetyl)-L-alaninyl] amino-2 ,4-dioxo- 1, 5-bis-( 1methylethyl)-2 5-tetrahydro- 1H-i 3-[N 5-difluorophenylacetyl)-(R)-2-thienylglycinyllamino-2 ,4-dioxo- 1, 5-bis-(l1-methylethyl)-2.3 ,4,5-tetrahydro-l1H-i, 3-[N '-(cyclopropylacetyl)-R-2-thienylglycinyl]amino-2 ,4-dioxo- 1, (1 -methylethyl)-2 ,3,4 ,5-tetrahydro-l1H-i, 3-[N '-(cyclopentylacetyl)-R-2-thienylglycinyllamino-2 ,4-dioxo- 1,5-bis-( 1methylethyl)-2,3,4, 5-tetrahydro- 1H-i 3-[N 5-difluorophenylacetyl)-L-alaninyl] amino-2 ,4-dioxo- 1, methyl-2,3,4, 5-tetrahydro7 1H- 3-[N ,5-difluorophenyl-cr-hydroxyacetyl)-L-alaninyllamino-2 ,4-dioxo- 1 ,5-bis-methyl-2 5-tetrahydro-l1H-i, 3- ,5-difluorophenylacetyl)-L-alaninyljamino-2 ,4-dioxo- 1,5-bis-(2methylpropyl)-2 ,3 ,4,5-tetrahydro- 1H-i, 3- -(cyclopentylacetyl)-L-alaninyl] amino-2 ,4-dioxo- 1,5-bis-(2methylpropyl)-2,3,4. 5-tetrahydro-l1H-i, WO 98/28268 PC.F/US97/22986 71 3-[N '-(cyclopropylacetyl)-L-alaninyl] -amino-2 ,4-dioxo- 1, 5-bis-(2methylpropyl)-2, 3,4,5-tetrahydro- 1 H-i1, 3- ,5-difluorophenylacetyl)-S-2-phenylglycinyl] -amino-2 ,4-dioxo- 1, 5-bis-(2-methylpropyl)-2 5-tetrahydro- 1H-i, 3-[N 5-difluorophenylacetyl)-L-alaninyl]-amino-2 ,4-dioxo- (cyclopropylmethyl)-2 5-tetrahydro- 1 H-i 3-[N '-(cyclopentylacetyl)-L-alaninyl]-amino-2 ,4-dioxo- 1, (cyclopropylmethyl)-2 ,3 ,4,5-tetrahydro- 1H- -(cyclopentyl-ca-hydroxyacetyl)-L-alaninyl]-amino-2 ,4-dioxo- bis-(cyclopropylmethyl)-2 ,3,4 ,5-tetrahydro- LH- 1 3-[N 5-difluorophenylacetyl)-L-alaninyl] -amino-2 ,4-dioxo- (2 ,2-dimethylpropyl)-2 ,3 ,4 ,5-tetrahydro-l1H-i ,5-difluorophenyl-cx-hydroxyacetyl)-L-alaninyl]-amino-2 ,4-dioxo- 1 ,5-bis-(2,2-diinethylpropyl)-2 ,3 ,4,5-tetrahydro- 1 H-i -(cyclopentylacetyl)-L-alaninyllainino-2 ,4-dioxo- 1, 5-bis-(2 12dimnethylpropyl)-2,3 ,4,5-tetrahydro- I H-i 3-[N '-(cyclopentyl-ca-hydroxyacetyl)-L-alaninyl] amino-2 ,4-dioxo- 1, (2 ,2-dimethylpropyl)-2 ,3 ,4,5-tetrahydro-l1H-i 3-[N ,5-difluorophenylacetyl)-L-alaninyl]-amino-2 ,4-dioxo- 1, phenyl-2, 3,4,5-tetrahydro- 1 H-i 3-[N '-(cyclopentylacetyl)-L-alaninyllamino-2 ,4-dioxo- 1, 2,3,4, 5-tetrahydro- IH- 1 ,-benzodiazepine 3-[N '-(cyclopentyl-a-hydroxyacetyl)-L-alaninyl]-aniino-2 ,4-dioxo- bis-phenyl-2 ,3 ,4,5-tetrahydro- iH- 3-(N ,5-difluorophenylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1-methyliH- 1,4-benzodiazepin-2-one 5- -(cyclopentylacetyl)-L-alaninyl }-amino-7-methyl-5, 7-dihydro-6Hdibenz[b,djazepin-6-one '-(3-cyclopentylpropionyl)-L-alaninyl} -amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b,d] azepin-6-one 5-f{N'-(cyclohexylacetyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,dlazepin-6-one WO 98/28268 PCT1US97/22986 72 '-(t-butylacetyl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,djazepin-6-one N' -(phenylacetyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,djazepin-6-one '-(3-bromophenylacetyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b ,d~azepin-6-one 5-{N '-(3-fluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro- 6H-dibenzllb,djazepin-6-one N' -(3-chlorophenylacetyl)-L-alaninyl}-aniino-7-methyl-5 ,7-dihydro- 6H-dibenz[b,d] azepin-6-one N' -(3-(trifluoromethyl)phenylacetyl)-L-alaninyl}-amino-7-methyl-s ,7dihydro-6H-dibenz[b,djazepin-6-one {N '-(4-fluorophenylacetyl)-L-alaninyl} -amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b,d]azepin-6-one '-(hexanoyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,djazepin-6-one 5-{N '-(heptanoyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,d]azepin-6-one 5-{3 ,4-difluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b,d~azepin-6-one '-(cyclopropylacetyl)-L-alaninyl} -amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,d]azepin-6-one '-(2-cyclopentene-l1-acetyl)-L-alaninyl} -amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b,d]azepin-6-one '-(3-cyclohexylpropionyl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b,d]azepin-6-one 5-{N '-(isovaleryl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,dljazepin-6-one N' -(citronellyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,dlazepin-6-one 5-{N'-(3-benzoylpropionyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,d] azepin-6-one WO 98/28268 PCTIUS97/22986 73 '-(2-chlorophenylacetyl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b azepin-6-one '-(4-pentenoyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,d]azepin-6-one -(valeryl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,d]azepin-6-one 5-{N '-(2-thiophenecetyl)-L-alaninyl}-amino-7-methyl- 7-dihydro-6Hdibenz[b,dlazepin-6-one '-(4-(2-thienyl)butyryl)-L-alaninyl} -amino-7-methyl-5 ,7-dihydro-6Hdibenz~b,djazepin-6-one -(4-(4-nitrophenyl)butyIy)-L-alaninyl}-amino-7-methyl.5 ,7dihydro-6H-dibenz[b,d]azepin-6-one '-(2,4-difluorophenylacetyl)-L-alaninyl }-amino-7-methyl-5 ,7dihydro-6H-dibenz[b,dlazepin-6-one 6 -difluorophenylacetyl)-L-alaninyl}-aniino-7-methyl.s,7dihydro-6H-dibenz[b,d] azepin-6-one 5-{N'-(4-isopropylphenylacety)-L-alaniny1}-amino-7-methyls ,7-dihydro- 6H-dibenz[b ,djazepin-6-one {N -adamantaneacetyl)-L-alaninyl)}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,d]azepin-6-one 5-f{N'-(5-cyclohexanepentanoyl)-L-alaninyl)}-aniino-7-methyl-5 ,7-dihydro- 6H-dibenz[b, djazepin-6-one '-((methylthio)acetyl)-L-alaninyl}-amino-7-methyl-s ,7-dihydro-6Hdibenzb,d]azepin-6-one {N'-(2-thiophenepentanoyl)-L-alaninyl}-amino-7-methy1-s ,7-dihydro- 6H-dibenz[b ,d]azepin-6-one 5-{N '-(2-norbomaneacety)-L-alaninyl}-anmino-7-methyl-s ,7-dihydro-6Hdibenz[b,d]azepin-6-one 5-difluorophenylacetyl)-4-ethylnoreucinyl} -amino-7-methyl- ,7-dihydro-6H-dibenzllb,d]azepin-6-one ,5-difluorophenylacetyl)-4-methylnorleucinyl }-amino-7-methyl- 7-dihydro-6H-dibenz [b ,djazepin-6-one WO 98UM26 PCT1US97/22986 74 ,5-difluorophenylacety1)-3-cyclopropylaIaninyl-amino-7-methyl.
7-dihydro-6H-dibenz[b,d]azepin-6-one 5-difluorophenylacetyl)-4-cyclohexylhomoalaninyl }-amino-7methyl- 7-dihydro-6H-dibenz[b ,djazepin-6-one ,5-difluorophenylacetyl)-6-fluoronorleucinyl}-amino-7-methyl- ,7-dihydro-6H-dibenz[b ,d]azepin-6-one 5-{N 5-difluorophenylacetyl)-4-methylnorleucinyl }-amino-7-methyl- 7-dihydro-6H-dibenz[b,djazepin-6-one '-(cyclohexylacetyl)-4-ethylnorleucinyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz~b ,dlazepin-6-one {N'-(cyclopropylacetyl)-4-ethylnorleucinyl }-amino-7-methyl-5 ,7dihydro-6H-dibenz[b,djazepin-6-one -(isovaleryl)-4-ethylnorleucinyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,d]azepin-6-one '-(3-(trifluoromethyl)phenylacetyl)-4-ethylnorleucinyl }-amino-7methyl-S ,7-dihydro-6H-dibenz[b ,dlazepin-6-one ,4-difluorophenylacety)-4-ethylnorleucinyl}-arnino-7-methyl-5 .7dihydro-6H-dibenz[b ,d]azepin-6-one ,4-difluorophenylacety)-4-ethylnorleucinyl)}-amino-7-methyl-5 ,7dihydro-6H-dibenzllb,d]azepin-6-one -(3-fluorophenylacetyl)-4-methylnorleucinyl)}-amino-7-methyl-5 ,7dihydro-6H-dibenz[b azepin-6-one '-(cyclopentylacetyl)-4-methylnorleucinyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz[b,djazepin-6-one '-(cyclohexylacetyl)-4-methylnorleucinyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz[b ,d]azepin-6-one 5-f N' -(cyclopropylacetyl)-4-methylnorleucinyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz[b,d]azepin-6-one '-(2-thiopheneacetyl)-4-methylnorleucinyl aniino-7-methyl-5 .7dihydro-6H-dibenz[b azepin-6-one N'-(isovaleryl)-4-methylnorleucinyl }-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,djazepin-6-one WO 9828268 PCT/US97122986 75 '-(3-(trifluoromethyl)phenylacetyl)-4-methylnoreucinyl} -amino-7methyl-S ,7-dihydro-6H-dibenz[b,d]azepin-6-one '-(4-fluorophenylacetyl)-4-niethylnoreucinyl }-amino-7-methyl-5 ,7dihydro-6H-dibenz[b ,dlazepin-6-one ,4-difluorophenylacetyl)-4-methylnorleucinyl }-amino-7-methyl- 7-dihydro-6H-dibenz azepin-6-one 5-f{N' ,4-difluorophenylacetyl)-4-methylnoreucinyl }-amino-7-methyl- 7-dihydro-6H-dibenz[b,dlazepin-6-one '-(3-fluorophenylacetyl)-4-cyclohexylhomoalaninyl}-amino-7methyl-S ,7-dihydro-6H-dibenz[b,dlazepin-6-one {N'-(cyclopentylacetyl)-4-cyclohexylhomoalaninyl}-amino-7-methyl- 7-dihydro-6H-dibenz[b,dlazepin-6-one '-(cyclohexylacetyl)-4-cyclohexylhomoalaninyl}-ainino-7-methyl- 5 ,7-dihydro-6H-dibenz[b ,d]azepin-6-one '-(cyclopropylacetyl)-4-cyclohexylhomoalaninyl}-amino-7-methyl- ,7-dihydro-6H-dibenz~b ,djazepin-6-one -(isovaleryl)-4-cyclohexylhomoalaninyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz[b,d]azepin-6-one {N '-(4-fluorophenylacetyl)-4-cyclohexylhomoalaninyl} -amino-7methyl-S ,7-dihydro-6H-dibenz[b,d]azepin-6-one ,4-difluorophenylacetyl)-4-cyclohexylhomoalaninyl }-amino-7methyl-S ,7-dihydro-6H-dibenz[b,d] azepin-6-one ,4-difluorophenylacetyl)-4-cyclohexylhomoalaninyl} -amino-7methyl-S ,7-dihydro-6H-dibenz[b, d]azepin-6-one '-(3-fluorophenylacetyl)-6-fluoronorleucinyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz~b ,dlazepin-6-one 5-{N '-(cyclopentylacetyl)-6-fluoronorleucinyl}-amino-7-methyl-5 ,7dihydro-6H-dibenzjlb,dlazepin-6-one '-(cyclohexylacetyl)-6-fluoronorleucinyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz[b,djazepin-6-one 5-{N'-(cyclopropylacetyl)-6-fluoronorieucinyl-amino-7-methyl-5 ,7dihydro-6H-dibenz~b,dlazepin-6-one WO 98M2268 PCTIUS97/22986 76-- '-(isovaleryl)-6-fluoronorleucinyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenzb,djazepin-6-one 5-{N'-(3-(trifluoromethyl)phenylacetyl)-6-fluoronorleucinyl} -amino-7methyl-S ,7-dihydro-6H-dibenz[b,dlazepin-6-one* {N '-(4-fluorophenylacetyl)-6-fluoronorleucinyl} -amino-7-methyl-5 ,7dihydro-6H-dibenz[b,d]azepin-6-one 5-{N ,4-difluorophenylacetyl)-6-fluoronorleucinyl} -aniino-7-methyl- 7-dihydro-6H-dibenz~b,d] azepin-6-one ,4-difluorophenylacetyl)-6-fluoronorleucinyl}-aniino-7-methyl- 7-diliydro-6H-dibenz[b,djazepin-6-one '-(4-methoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b,d]azepin-6-one -(3-(4-methoxyphenyl)propionyl)-L-alaninyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz[b,djazepin-6-one 1-naphthylacetyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,d]azepin-6-one 5- ,4-methylenedioxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz[b,d] azepin-6-one -(hydrocinnamyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,d]azepin-6-one -(octanoyl)-L-alaninyl}-aniino-7-methyl-5 ,7-dihydro-6Hdibenz[b,d]azepin-6-one N'-(3-(3-hydroxyphenyl)propionyl)-L-alaninyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz[b,dlazepin-6-one '-(3-(4-methylphenyl)propionyl)-L-alaninyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz[b,d]azepin-6-one 5-{N'-(3-(4-chlorophenyl)propionyl)-L-alaninyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz[b ,d]azepin-6-one -(3-phenylbutyryl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b azepin-6-one -(3-(4-hydroxyphenyl)propionyl)-L-alaninyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz[b azepin-6-one WO 98/28268 PCTIUS97/22986 77 5-trifluorophenylacetyl)-L-alaninyl} -amino-7-methyl-5 .7dihydro-6H-dibenz[b,d]azepin-6-one '-(4-(4-methoxypheny)butyry)-L-alaninyl}-amino-7-methy1l 7dihydro-6H-dibenz[b,dlazepin-6-one {N'-(3-(methoxycarbonyl)propionyl)-L-alaninyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz[b,d]azepin-6-one 5-f{N '-(4-phenylbutyryl)-L-alaninyl}-amino-7-methyl-5, 7-dihydro-6Hdibenz[b,d] azepin-6-one '-(3-(berizylthio)-propionyl)-L-alaninyl} -aniino-7-methyl-5 ,7dihydro-6H-dibenz[b, dlazepin-6-one '-(3-methylpentanoyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,d]azepin-6-one '-(7-carbomethoxyheptanoyl)-L-alaninyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz[b,dlazepin-6-one 5-f{N'-(2-indanylacetyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,djazepin-6-one 5-{N '-(5-carbomethoxypentanoyl)-L-alaninyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz[b ,dlazepin-6-one 5-f{N'-(2-methyl-3-Benzofuranacetyl)-L-alaninyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz[b ,d]azepin-6-one '-(propionyl)-L-alaninyl}-aniino-7-methyl-5 ,7-dihydro-6Hdibenz[b,d]azepin-6-one '-'(3-methoxypropionyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b,dlazepin-6-one '-(3-(4-fluorophenyl)propionyl)-L-alaninyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz~b ,djazepin-6-one 5-{N '-(3-(4-fluorophenoxy)propionyl)-L-alaninyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz~b azepin-6-one '-(3-pentenoyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,d]azepin-6-one ,4-dichlorophenoxy)butyryl)-L-alaninyl} -amino-7-methyl-5 .7dihydro-6H-dibe'nz[b,dlazepin-6-one WO 98/28268 PTU9/28 PCT/US97/22986 78 3-dichlorophenoxyacetyl)-L-alaninyl}-amino-7-methyl-5 .7dihydro-6H-dibenz[b,d]azepin-6-one 5-{N'-(3-(4-chlorobenzoyl)propionyl)-L-alaninyl}-amino-7-methyl-5 ,7dihydro-6H-dibenzllb,dlazepin-6-one 5-{N'-(4'-fluorosuccinanilyl)-L-alaninyl} -amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b,dlazepin-6-one 5-{N'-(N-(diphenylmethyl)glutaramyl)-L-alaninyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz[b,d]azepin-6-one '-(2-fluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b ,djazepin-6-one -(cyanoacetyl)-L-alamnyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,dlazepin-6-one 5-{N'-(succinanilyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,d]azepin-6-one ,4-dichlorophenoxyaceyl)-L-alaninyl }-amino-7-methyl-5 .7dihydro-6H-dibenz[b ,djazepin-6-one 5-{N'-(2-nitrophenylacetyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,d]azepin-6-one '-(beta-propylhydrocinnamy l)-L-alaninyl}-amino-7-methyl-5 .7dihydro-6H-dibenz[b,d]azepin-6-one '-(3-(2,4-dimethylbenzoyl)propionyl)-L-alaninyl}-amino-7-methyl- ,7-dihydro-6H-dibenz[b,d]azepin-6-one '-(2-fluoro-3-(trifluoromethyl)phenylacetyl)-L-alaninyl}-amino-7methyl-5 ,7-dihydro-6H-dibenz[b ,djazepin-6-one ,4,6-trifluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz[b,d]azepin-6-one 5-{N'-(4-fluoro-2-(trifluoromethyl)phenylacetyl)-L-alaninyl}-amino-7methyl-S ,7-dihydro-6H-dibenz[b,djazepin-6-one 5-{N'-(2-fluoro-4-(trifluoromethyl)phenylacetyl)-L-alaninyl}-amino-7methyl-S ,7-dihydro-6H-dibenz[b ,dI azepin-6-one 5-{N'-(4-hydroxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b,dlazepin-6-one WO 98t28268 PCTUS97/22986 79 -(4-methoxyphenoxyacetyl)-L-alaninyl}-amino-7-methyl-5 .7dihydro-6H-dibenz[b ,dlazepin-6-one {N '-(2-methoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b,dlazepin-6-one '-(2-bromophenylacetyl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b ,dlazepin-6-one, 5-f{N '-(4-benzyloxyphenoxyacetyl)-L-alaninyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz[b ,d]azepin-6-one N'-(4-hydroxyphenoxyacetyl)-L-alaninyl}-amino-7-methyl- 7dihydro-6H-dibenzlb,dlazepin-6-one '-(levulinyl)-L-alaninyl}-ainino-7-methyl-5 ,7-dihydro-6Hdibenz[b,dlazepin-6-one '-(2-hydroxyphenylacetyl)-L-alaninyl} -amino-7-methyl-5 ,7-dihydro- 6H-dibenz~b,djazepin-6-one ,4-dimethoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5 .7dihydro-6H-dibenz[b ,dlazepin-6-one 5-{N '-(3-(4-methoxybenzoyl)propionyl)-L-alaninyl }-amino-7-methyl-5 .7dihydro-6H-dibenz[b ,dlazepin-6-one '-(3-(4-phenylbenzoyl)propionyl)-L-alaninyl} -amino-7-methyl-5 .7dihydro-6H-dibenz[b,d]azepin-6-one '-(3-hydroxyphenylacetyl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b ,d]azepin-6-one N'-(N-acetyl-N-phenylglycinyl)-L-alaninyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz~b ,djazepin-6-one '-(thiophene-3-acetyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b dazepin-6-one 5-{N '-(6-phenylhexanoyl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,d] azepin-6-one {N '-(4-cyclohexanebutyryl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro- 6H-dibenzllb,dlazepin-6-one {N 5-trifluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5 .7dihydro-6H-dibenz[b ,djazepin-6-one WO 98/8268 PCT1US97/22986 5-trifluorophenylacetyl)-L-alaninyl }-amino-7-methyl-5 ,7dihydro-6H-dibenz[b ,d]azepin-6-one '-(vinylacetyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro-6f1dibenz[b,dlazepin-6-one '-(3-methylthiopropionyl)-L-alaninyl} -amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b,d]azepin-6-one 5-{N '-(3-nitrophenylacetyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b ,dI azepin-6-one '-(N-tert-butylsuccinaniyl)-L-alaninyl} -amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b,d]azepin-6-one N' -(4-bromophenylacetyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b ,dlazepin-6-one '-(3-(4-fluorobenzoyl)propionyl)-L-alaninyl}-amino-7-methyl-5 .7dihydro-611-dibenz[b,djazepin-6-one -(o-chlorophenoxyacetyl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b,d]azepin-6-one 5- {N'-(p-tolylacetyl)-L-alaninyl}-aniino-7-methyl-5 ,7-dihydro-6Hdibenz[b,dlazepin-6-one {N '-(m-tolylacetyl)-L-alaninyl)}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b ,d]azepin-6-one ,4-dichlorophenylacetyl)-L-alaninyl }-amino-7-methyl-5 ,7dihydro-6H-dibenz jb ,dlazepin-6-one '-(4-chlorophenoxyacetyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro- 6H-dibenzb,dlazepin-6-one -(3-methylphenoxyacetyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b ,dlazepin-6-one 5-{N '-(4-isopropylphenoxyacetyl)-L-alaninyl}-aniino-7-methyl-5 ,7dihydro-6H-dibenz[b ,d]azepin-6-one N' -(4-phenoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b,d] azepin-6-one '-(phenylmercaptoacetyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b,d] azepin-6-one WO 98/28268 PCT/US97/22986 81 '-(4-ethoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-s ,7-dihydro- 6H-dibenz[b azepin-6-one N' 5-dimethoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5 .7dihydro-6H-dibenz[b ,dlazepin-6-one {N '-(o-tolylacetyl)-L-alaninyl)}-amino-7-methyl-5 ,7-dihydro-6Hdibenz~b,dlazepin-6-one 3-diphenylpropionyl)-L-alaninyl)}-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b,djazepin-6-one N' -(3-phenoxypropionyl)-L-alaninyl} -amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,d]azepin-6-one {N '-(4-(trifluoromethyl)phenylacetyl)-L-alaninyl} -amino-7-methyl-5 .7dihydro-6H-dibenz[b,djazepin-6-one N' -((4-methylphenoxy)acetyl)-L-alaninyl}-amino-7-methyl-5 .7dihydro-6H-dibenz~b,d] azepin-6-one {N'-(2-phenoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b ,dlazepin-6-one N' -(3-phenoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b ,djazepin-6-one ,4-dichlorophenoxyacetyl)-L-alaninyl} -amino-7-methyl-5 ,7dihydro-6H-dibenz[b,dlazepin-6-one N' -(4-fluorophenoxyacetyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b ,dlazepin-6-one ,4,5-trimethoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz[b ,d]azepin-6-one {N ,4-dichlorophenylacetyl)-L-alaninyl} -amino-7-methyl-5 ,7dihydro-6H-dibenz[b,d]azepin-6-one 5-{N '-(4-thianaphthenacetyl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b,d]azepin-6-one {N'-(methoxyacetyl)-L-alaninyl}-amino-7-methyl-s ,7-dihydro-6Hdibenz[b,d] azepin-6-one '-(ethoxyacetyl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,d]azepin-6-one WO 98/28268 PCTJ'US97/22986 82 -(phenoxyacetyl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b ,d]azepin-6-one -(3-methoxyphenoxyacetyl)-L-alaninyl} -amino-7-methyl-5 ,7dihydro-6H-dibenz[b ,d~azepin-6-one {N '-(4-butoxyphenylacetyl)-L-alaninyl} -amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b,d]azepin-6-one N'-(3-(2-methoxyphenyl)propionyl)-L-alaninyl }-amino-7-methyl-5 ,7dihydro-6H-dibenz[b ,d]azepin-6-one N N-dimnethylsuccinamyl)-L-alaninyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz[b ,d]azepin-6-one ,4-methylenedioxyphenyl)propionyl)-L-alaninyl} -amino-7methyl-S ,7-dihydro-6H-dibenz[b ,dlazepin-6-one -(2-chloro-6-fluoroplienylacetyl)-L-alaninyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz[b,d] azepin-6-one ,5-difluorophenylacetyl)-L-alaninyl }-amino-7-methyl-5 ,7dihydro-6H-dibenz[b dazepin-6-one 5-f ,6-pentafluorophenoxyacetyl)-L-alaninyl}-amino-7-methyl- 7-dihydro-6H-dibenz[b,dlazepin-6-one ,5-bis(trifluoromethyl)phenylacetyl)-L-alaninyl}-amino-7-methyl- 7-dihydro-6H-dibenz[b ,djazepin-6-one ,5-dimethylphenoxyacetyl)-L-alaninyl }-amino-7-methyl-5 .7dihydro-6H-dibenz[b,d]azepin-6-one N '-(4-chlorophenylacetyl)-L-alaninyl)}-amino-7-methyl-5 ,7-dihydro- 6H-dibenzb,d]azepin-6-one '-(3-chlorophenoxyacetyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b ,dlazepin-6-one 5-{N '-(benzolbthiophene-3-acetyl)-L-alaninyl}-amino-7-methyl-5 .7dihydro-6H-dibenz[b, dlazepin-6-one ,5-dimethoxyphenylacetyl)-L-alaninyl }-amino-7-methyl-5 ,7dihydro-611-dibenz[b,d] azepin-6-one ,5-dimethylphenylacetyl)-L-alaninyl} -amino-7-methyl-5 ,7dihydro-6H-dibenz[b dazepin-6-one WO 98/28268 PCT1US97/22986 83 -(mesitylacetyl)-L-alaniny1}-amino-7-methyl 7-dihydro-6Hdibenz[b ,d]azepin-6-one {N '-(4-biphenylacetyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,d]azepin-6-one {N '-(N-(tert-butoxycarbonyl)-3-aminopropionyl)-L-alaninyl} -amino-7methyl-S. 7-dihydro-6H-diberiz[b ,d]azepin-6-one 5- {N '-(trans-styrylacetyl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b ,djazepin-6-one 5-{N'-(4-acetamidobutyryl)-L-alaniny}-amino-7-methyls ,7-dihydro-6Hdibenz[b, dlazepin-6-one 3 2 -chlorophenyl)propionyl)-L-alaninyl}-amino-7-methyls .7dihydro-6H-dibenzlb ,d]azepin-6-one '-(butyryl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenzllb,d]azepin-6-one -(trans-3-hexenoyl)-L-alaninyl} -amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,d]azepin-6-one N' -(5-phenylvaleryl)-L-alaninyl} -amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,dI azepin-6-one {N 3 -methoxyphenyl)propionyl)-L-alaninyl}-amino-7-methyl- 7dihydro-6H-dibenz[b ,dlazepin-6-one {N '-(4-chloro-beta-methylhydrocinnamyl)-L-alaninyl}-amino-7-methyl- 7-dihydro-6H-dibenz[b ,d]azepin-6-one {N '-(3-(trifluoromethyl)butyryl)-L-alaninyl}-amino-7-methyl-s ,7dihydro-6H-dibenz[b,dlazepin-6-one {N '-(alpha-naphthoxyacetyl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b, d] azepin-6-one 5- {N '-(3-(4-phenoxybenzoyl)propionyl)-L-alaninyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz[b ,dlazepin-6-one (N'-(3-(2-trifluoromethylbenzoyl)propiony)-L-alaninyl} -amino-7methyl-S ,7-dihydro-6H-dibenz[b ,dlazepin-6-one {N '-(3-benzoylamino-3-phenyl-propionyl)-L-alaninyl)}-amino-7-methyl- ,7-dihydro-6H-dibenz[b,dlazepin-6-one WO 98/28268 PCT[rJS97/22986 84-- -(4-(hydroxyimino)pentanoyl)-L-alaninyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz~b, dlazepin-6-one -methylglutaranilyl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b ,dlazepin-6-one {N'-((4-(4-ethyl-phenoxy)-phenoxy)-acetyl)-L-alaninyl} -amino-7methyl-S ,7-dihydro-6H-dibenzllb,d]azepin-6-one 5-{N '-(3-benzoyl-3-phenylpropionyl)-L-alaninyl} -amino-7-methyl-5 ,7dihydro-6H-dibenz[b azepin-6-one '-(4-(hydroxymethyl)phenoxyacetyl)-L-alaninyl }-amino-7-methyl- ,7-dihydro-6H-dibenzlb,d]azepin-6-one ,4,4-trifluorobutyryl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b ,dljazepin-6-one N'-(3-isobutyrylamino-3-phenyl-propionyl)-L-alaninyl} -amino-7methyl-S ,7-dihydro-6H-dibenz jb azepin-6-one '-((2-methylphenoxy)acetyl)-L-alaninyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz[b ,d]azepin-6-one 5-{N'-(3-(phenylsulfonyl)propionyl)-L-alaninyl}-amino-7-methyl-5 ,7dihydro-6H-diberiz[b, dlazepin-6-one 5-{N'-(4-nitrophenylacetyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b ,djazepin-6-one N' -(3-ethoxypropionyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b ,d]azepin-6-one 3-difluoromandelyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b,d]azepin-6-one '-(2,6-difluoromandelyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro- 6H-dibenzlb ,diazepin-6-one 5-f{N'-(4-fluoromandelyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,d]azepin-6-one ,5-difluoromandelyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro- 6H-dibenzlb ,dlazepin-6-one '-(beta-phenyllactyl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b ,d]azepin-6-one WO 98/28268 PTU9/28 PCTIUS97/22986 85 {N'-(mandelyl }-amino-7-methyl-5 ,7-dihydro-6H-dibenz[b,d]azepin-6one -(p-chloromanclelyl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,djazepin-6-one N' -(L-alpha-hydroxyisocaproyl)-L-alaninyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz[b ,d]azepin-6-one 5-{N '-(4-bromomandelyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b ,d]azepin-6-one N' +)-lactyl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,d]azepin-6-one N' -(D-3-phenyllactyl)-L-alaninyl)}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b ,dlazepin-6-one N' -(5-methylhexanoyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b azepin-6-one ,5-difluorophenylacetyl)-L-methioninyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz[b,d]azepin-6-one 5-{N ,5-difluorophenylacetyl)-L-2-phenylglycinyl}-amino-7-methyl- 7-dihydro-6H-dibenz[b,d]azepin-6-one 5-difluorophenylacetyl)-L-leucinyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz[b azepin-6-one ,5-difluorophenylacetyl)-L-2-cyclohexylglycinyl }-amino-7methyl-S ,7-dihydro-6H-dibenz[b,dlazepin-6-one ,5-difluorophenylacetyl)-L-threoninyl }-amino-7-methyl-5 ,7dihydro-6H-dibenz[b azepin-6-one 5-difluorophenylacetyl)-L-alpha-(2-thienyl)gly cinyl}-amino-7methyl- 7-dihydro-6H-dibenz[b,d] azepin-6-one 5- {N '-(2-thiopheneacetyl)-L-methioninyl}-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b ,dlazepin-6-one -(2-thiopheneacetyl)-L-2-phenylglycinyl)}-amino-7-methyl-5 ,7dihydro-6H-dibenz[b ,djazepin-6-one -(2-thiopheneacetyl)-L-Ieucinyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b ,d]azepih-6-one WO 98/28268 PCTIUS97/22986 86 N' -(2-thiopheneacetyl)-L-2-cyclohexylglycinyl} -amino-7-methyl-5 ,7dihydro-6H-dibenz[b ,dljazepin-6-one {N '-(2-thiopheneacetyl)-L-threoninyl }-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,d]azepin-6-one '-(2-thiopheneacetyl)-L-alpha-(2-thienyl)glycinyl}-amino-7-metiyl- ,7-dihydro-6H-dibenz[b,dlazepin-6-one 5-{N '-(isovaleryl)-L-methioninyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenzb, d]azepin-6-one '-(isovaleryl)-L-2-phenylglycinyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,d]azepin-6-one N'-(isovaleryl)-L-leucinyl}-amino0-7-methyl-5 ,7-dihydro-6Hdibenz[b,djazepin-6-one '-(isovaleryl)-L-2-cyclohexylglycinyl}-aniino-7-methyl-5 ,7-dihydro- 6H-dibenz[b,d]azepin-6-one {N '-(isovaleryl)-L-threoninyl} -amino-7-methyl-5 ,7-dihydro-6Hdibenzllb -d]azepin-6-one 5-f{N' -(isovaleryl)-L-alpha-(2-thienyl)glycinyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz[b,d]azepin-6-one {N '-(phenylacetyl)-L-methioninyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,d]azepin-6-one '-(phenylacetyl)-L-2-phenylglycinyl }-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b,djazepin-6-one N' -(phenylacetyl)-L-leucinyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,dlazepin-6-one 5-f{N'-(phenylacetyl)-L-2-cyclohexylglycinyl}-amino-7-methyl-5 ,7dihydro-6H-dibenz~b,d] azepin-6-one 5-f N '-(phenylacetyl)-L-threoninyl}-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,d]azepin-6-one '-(phenylacetyl)-L-alpha-(2-thienyl)glycinyl }-amino-7-methyl-5 ,7dihydro-6H-dibenz[b,d]azepin-6-one WO 98/28268 PCT/US97/22986 87 Preferred cyclic groups defined by W and include cycloalkyl, lactone, lactam, benzazepinone, dibenzazepinone and benzodiazepine groups. In one preferred embodiment, the cyclic group defined by W and forms a cycloalkyl group of the formula: -CH wherein T is selected from the group consisting of alkylene and substituted alkylene.
A preferred cycloalkyl group is represented by the formula: (V)t (Ra)w V)t wherein each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like; R a is selected WO 98/28268 PCTIUS97/22986 88 from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; t is an integer from 0 to 4; and w is an integer from 0 to 3.
Preferably t is an integer from 0 to 2 and, more preferably, is an integer equal to 0 or 1.
In another preferred embodiment, the cyclic group defined by W, together with is a ring of the formula:
T
-C(H)p
CH
OH
or
T
-C(H)p
CH
CHT
SH
wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R 2
Z),R
2 and -ZR- 21 WO 98/28268 PCT/US97/22986 89 where Z is a substituent selected from the group consisting of and
>NR
20 each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is or any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3.
Particularly preferred alcohol or thiol substituted groups include (V)t (Ra)W
OH
(V)t (Ra)w t(V) HOa
HO
OH
OH
wherein each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxyialkyl, cyano, halo, nitro, heteroaryl,
I
WO 98/28268 PCTUS97I22986 90 thioalkoxy, substituted thioalkoxy, trihalomethyl and the like; R' is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; t is an integer from 0 to 4; and w is an integer from 0 to 3.
Preferably t is an integer from 0 to 2 and, more preferably, is an integer equal to 0 or 1.
Yet another preferred embodiment of the cyclic group defined by W, together with is a ring of the formula:
T
C
-C(H)
or
T
-C(H)p
C
II
S
WO 98/28268 PCT/US97/22986 91 wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R 2 Z)qR 2 and -ZR 2 1 where Z is a substituent selected from the group consisting of and
NR
20 each R 2 0 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 2 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is or any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3.
Particularly preferred cyclic ketone and thioketone groups include: (Ra) (V)t wherein each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like; Ra is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, WO 98/28268 PCT/US97/22986 92 amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; t is an integer from 0 to 4; and w is an integer from 0 to 3.
Preferably t is an integer from 0 to 2 and, more preferably, is an integer equal to 0 or 1.
In another preferred embodiment, the cyclic group defined by W, together with forms a ring of the formula: -C(H)p -C(H)p
T
C/O
II
O
-T
I I
O
WO 98/28268 PCT/US97/22986 93 /11 -C(H)p
T
C/O
II
S
T
-C(H)p wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R 21 Z)qR 2 and -ZR 21 where Z is a substituent selected from the group consisting of and
NR
2 0 each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is or any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3.
Particularly preferred lactone and thiolactone groups include: WO 98/28268 PCTIUS9722986 94 (Ra)w wherein each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like; R" is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; t is an integer from 0 to 4; and w is an integer from 0 to 3.
Preferably t is an integer from 0 to 2 and, more preferably, is an integer equal to 0 or 1.
In another preferred embodiment, the cyclic group defined by W and forms a lactam ring of the formula:
T
-C(H)p C\ 0 WO 98/28268 PCTUS97/22986 95 or a thiolactam ring of the formula:
T
C(H)p C ffCwherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R 21
Z),R
2 and -ZR 21 where Z is a substituent selected from the group consisting of and
NR
20 each R 2 0 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 2 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is or any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3.
WO 98/28268 PCT/US97/22986 96 Particularly preferred lactamn and thiolactam groups include: 0 (V)t
R
N N 0 Rb 0 Rb Mt) (Ra)w 4NRa 0 0D 'Rb VtM WO 98/28268 PC'rIUS97/22986 (Ra)w (Ra)w
N
o RbN o Rb 0 ~Rb 0 R I (Ra)w% (Ra)w
N
oN\R 0
N
RRb 0 Rb WO 98/28268 PCT/US97/22986 98 Rb Rc N N 0
R
Rb
A,"
N I N RcO \b wherein A-B is selected from the group consisting of alkylene, alkenylene, substituted alkylene, substituted alkenylene and Q' is oxygen or sulfur; each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like; R" is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; Rb is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, heteroaryl, heterocyclic, and the like; Rc is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl, and substituted cycloalkyl; t is an integer from 0 to 4; t' is an integer from 0 to 3; and w is an integer from 0 to 3.
Preferably t is an integer from 0 to 2 and, more preferably, is an integer equal to 0 or 1.
WO 98/28268 PCT/US97/22986 99 In another preferred embodiment, the cyclic group defined by W, together with forms a ring of the formula:
T
-C(H)p NR 20
CH
2 wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R2 2 Z)qR 2 and -ZR 21 where Z is a substituent selected from the group consisting of and
NR
20 each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 2 1 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is or any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3.
A still further preferred embodiment is directed to a ring group defined by W, together with of the formula:
T
-C(H)p 3CH o NR20R20
NR
20
R
20 WO 98/28268 PCT/US97/22986 100 wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R21Z),R 2 and -ZR 21 where Z is a substituent selected from the group consisting of and
NR
2 0 each R 2 0 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is or any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3.
This invention also provides for novel pharmaceutical compositions comprising a pharmaceutically inert carrier and a compound of the formula I above.
Still further, this invention provides for novel compounds of the formula
I:
R- NH C(H),
C
I
X
WO 98/28268 PCT/US97/22986 101 wherein R' is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic; W, together with forms a cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl, or substituted cycloalkenyl group wherein each of said cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl or substituted cycloalkenyl group is optionally fused to form a bi- or multi-fused ring system (preferably no more than 5 fused rings) with one or more ring structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group which, in turn, each of such ring structures are optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, nitro, cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, Nalkylamino, N,N-dialkylamino, N-substituted alkylamino, N-alkyl N-substituted alkylamino, N,N-disubstituted alkylamino, -NHC(O)R 4
-NHSOR
4
-C(O)NH
2
-C(O)NHR
4
-C(O)NR
4
R
4
-S(O)R
4
-S(O)
2
R
4
-S(O)
2
NHR
4 and -S(O) 2
NR
4
R
4 where each R 4 is independently selected from the group consisting of alkyl, substituted alkyl, or aryl; X is selected from the group consisting of oxo thiooxo hydroxyl thiol and hydro Y is represented by the formula: R2 /CH C NH 0 WO 98/28268 PCTUS97/22986 102 wherein each R' is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; Z is represented by the formula where T is selected from the group consisting of a bond covalently linking R 1 to oxygen, sulfur, -NR 5 where R 5 is hydrogen, acyl, alkyl, aryl or heteroaryl group; X' is hydrogen, hydroxy or fluoro, X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group; m is an integer equal to 0 or 1; n is an integer equal to 0, 1 or 2; p is an integer equal to 0 or 1 such that when p is zero, the ring defined by W and is unsaturated at the carbon atom of ring attachment to Y and when p is one, the ring is saturated at the carbon atom of ring attachment to Y, with the following provisos: A. when R' is 3,5-difluorophenyl, R 2 is -CH 3 Z is -CH 2 m is 1, n is 1, and p is 1, then W, together with >CH and does not form a 2-(S)-indanol group; B. when R' is phenyl, R 2 is -CH 3 Z is -CH 2 m is 1, n is 1, and p is 1, then W, together with CH and C=X, does not form a trans-2hydroxy-cyclohex-1-yl group; C. when R' is phenyl, Z is -CH 2 m is 1, n is 0, and p is 1, then W, together with >CH and C=X, does not form a gammabutyrolactone group or a 5,5-dimethyl-gammabutyrolactone group; D. when R' is phenyl, Z is -CH 2 m is 1, n is 0, and p is 1, then W, together with CH and C=X, does not form a e-caprolactam group; E. when R' is cyclopropyl, R 2 is -CH 3 Z is -CH 2 m is 1, n is 1, andp is 1, then W, together with >CH and does not form an Nmethylcaprolactam group; WO 98/28268 PCT/US97/22986 103 F. when R' is 4-chlorobenzoyl-CH 2
R
2 is -CH 3 Z is m is 1, n is 1, and p is 1, then W, together with CH and C does not form an 2, 3-dihydro-l1-methyl-5-phenyl- 1H-i ,4-benzodiazepin-2-one; when RI is 2-phenyiphenyl, RI is -CH 3 Z is -CH 2 M is 1, n is 1, and p is 1, then W, together with CH and C does not form an 7methyl-S ,7-dihydro-6H-dibeniz[b,d~azepin-6-one; H. when R' is CH 3
OC(O)CH
2 R 2 is -CH 3 Z is -CH 2 M is 1,1 n is 1, and p is 1, then W, together with CH and C does not form an 2 ,3-dihydro-l1-(t-butylC(O)CH 2 -)-5-(2-pyridyl)- 1 H-i ,4-benzodiazepin-2-one; 1. when R' is 4-ethoxyphenyl, 2,4,6-trimethyiphenyl, 4-phenyiphenyl,
CH
3
OC(O)CH
2 4-HOCH 2 -phenyl, 2,4, 6-trifluorophenyl, 2-trifluoromethyl-4fluorophenyl, or CH 3
R
2 is -CH 3 Z is -CH 2 M is 1, n is 1, and p is 1,then W, together with CH and C does not form a 2,3-dihydro- Ndiethylamino-CH 2 CH 2 -)-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one; J. when RI is 2,6-difluorophenyl, R 2 is -CH 3 Z is m is 1, n is 1, and p is 1, then W, together with CH and C does not form a 2, 3-dihydro-l1-(NN-diethylamino-CH 2
CH
2 -)-5-(2-pyridyl)- 111benzodiazepin-2-one, K. when misl1and nis 1, then
C
Il x does not equal cycloalkyl of from 3 to 8 carbon atoms optionally substituted with 1 to 3 alkyl groups.
WO 98/28268 PCT/US97/22986 104-- The products of this invention include mixtures of R,S enantiomers at any stereochemical center. Preferably, however, when a chiral product is desired, the chiral product corresponds to the L-amino acid derivative. In the formulas set forth herein, a mixture of R,S enantiomers at the stereochemical center is sometimes indicated by a squiggly line as per convention. Othertimes, no stereochemical designation is made at the stereochemical center and this also infers that a mixture of enantiomers is present.
Preferred compounds described herein include those set forth in the tables below: WO 98/28268 PCTIUS97/22986 105 TABLE 1-1 Ex. R R' R' 1-1 J_ 3,5-di-F--O- H H,H -CH, TABLE 2-1 [Ex.I R I X'i" R' R 2
/R
3 f n 2-1 3,5-di-F-0- H.H -CH 3 forms a fused 1 phenyl ring 2-2 3,5-di-F-0- H.H -CH, forms a fusedI Iphenyl ring 2-3 3,5-di-F-k- H.H -CH, forms a fused 1 ring 2-4 3,5-di-F-0- H,H -CH, H-,H 2 3,5-di-F-0- H,H -CH, forms a fused 2 ring 2-6 3.5-di-F-0- H.H -CH 3 forms a fused3 ring WO 98/28268 PCTIUS97/22986 106-- TABLE 2-2 xX H 0
N
R N
YIAH
HO
Ex. R X'I/X" R' 2-6 3,5-di-F-&6 H.H -CH, TABLE 2-3 xX H 0
N
R yJN
HO
WO 9=/8268 PCT/US97fl2986 107 TABLE 3-1 FEx.T R R2IR3 n 3-1 3,5-di-F-0- H,H -CH 3 forms a fused1 I ~~phenyl ring 3-2 4-H,H -CH, forms a fused 2 phenyl ring TABLE 3-2
H
0
H
Ri1 Ex. R X'IX" F3-3 3,5-di-F-0- H.H -CH WO 98/28268 PCTIUS97/22986 108 TABLE 4-1
R
2
R
3 Ex. R I R21/R 3 R_4_R 4-1 3.5-di-F--O-CH 2
-CH
3 H,H 0 4-2 3,4-di-CI-0- -CH 3 HH 0 4-3 cyclopernyl-CH 2
-CH
3 forms a fused -CH, -CH 3 1 phenyl ring 4-4 3,5-di-F-0-CHC(Q)- forms a fused -CH, -CH, I Iphenyl ring 1 WO 98t28268 WO 9828268PCT/US97/22986 109-- TABLE 5-1 Ex.R'Rl R2R3 R 4W' R
R
2 5-1 3,5-di-F-0-CH 2 -CH, H H H 0 5-2 3,5-di-F-0-CHC(O)- -CH, H H H HI 5-3 3.5-di-F-0-CHC(O)- -CH, H H H -CH,40 1 5-4 3,5-di-F-0-CH,C(O)- -CH, -CH, H H,H H 2 3,5-di-F-0-CH 2 -CH, H R 3 I W H I fused phenyl ring 5-6 3,5-di-F-0-CH,C(Q)- -CH 3 H R 3 IR' 4 -CH,o I fused phenyl ring 5-7 3,5-di-F-0-CHC(O)- *CH 3
R
2
/R
3 -H H I fused phenyl ring 5-8 3,5-di-F-0-CH 2 -CH, R 2
/R
3 H fused phenyl ring 5-9 3.5-di-F-0-CH,C(O)- -CH 3
R'/R
3 -CH, H 1 fused phenyl ring 5-10 3,5-di-F-0-CHC(O)- -CH, R 2 1R 3 -0 HI fused phenyl 5-11I 3,5-di-F-0-CH 2
-CH
3
R
2 1R 3 H H1 fused phenyl ring with 3-F su bs.
WO W28268 WO 9828268PCT1US97/22986 Ex. R' R' I R4 RS J__lw enl 5-12 3,5-di-F-0-CH,C(O)- -CH 3
R
2
/R
3 -H H fused phenyl ring with 4-F subs.
5-13 3.5-di-F-0-CH 1 -CH, R 2 1R 3 H -CH 2
CH
1
I
fused phenyl 5-14 3.5-di---CHC(Q)- -CH, Rz/R 3 -H -CH, fused phenyl 5-15 3,5-di-F-0k-CHC(O)- -CH, R 2
(R
3 -H HI fused phenyl ring with subs.
5-16 3,5-di---CHC(Q)- -CH 3
R
2
/R
3 H H1 fused phenyl ring with 4-46 subs.
5-17 3,5-di-F-40-CH 2 -CH, R 2 1R 3 H1 together with the pendent atoms form (9-aminofluroren-lyl)glycine 6-lactam 5-18 Ot-CHC(O)- -CH, H H H,H H 2 5-19 3,5-di---CHC(O)- -CH, H H H,H H 2 5-20 3.5-di-F-46-CH,C(O)- -CH 3 H H H,H -CH,O 2 5-21 3,5-di-F-0-CH 2
-CH
3 H H H.H 2-methoxy- 2 ethoxy 5-22 3.5-di-F-,O-CH,C(O)- -CH, H H H,H ethyl 2 5-23 -CH 3 H ethyl H.H H 2 5-24 -CH 3 H ethyl H,H H 2 5-25 -CH 3 H H H, H 2 benzyl 5-26 -CH, R 2
/R
3 H H -CHO 1 5-27 cyclopentyl-CH,C(Q)- -CH, H H H.1 -CHO 2 5-28 cyclopentyl-CH,C(O)- -0 H H H.1 -CHO 2 WO 98=8268 PCT/US97/22986 ill Ex.J R' jl R 2
R
3 R4/ j' 5-29 3.5-di-F-0-CH,C(O)- -CH, H H H,H -CH,CH,O 2 5-30 cyclopentyl-CH 2 -0 H H H,H -CH,CH~o 2 5-31 3.4-di-CI-40- -CH 3 H H H,H H 2 5-32 cyclopropyl-CH 2 -0 H H H.H -CH, 2 5-33 3,5-di-F-0-CH,C(O)- -CH, H H H,H, H 4
H.H
5-34 3,5-di-F-q0-CH 2 -CH, R 2 1R 3 H H HI fused phenyl ring with 4-benzyl subs.
5-35 3,5-di-F-45-CH,C(O)- -CH 3
R
2 1/R' -CH 2
HI
fused phenyl ring 5-36 3,5-di-F-40-CHC(O)- -CH, R 2
/R
3 -0 -CH, fused phenyl ~~ring 5-37 3,5-di-F-0k-CH,C(Q)- -CH, R 2
/R
3 pyrid- HI fused phenyl 2 -yI ring 5-38 3,5-di-F-46-CH,C(O)- -CH, R 3 pyrid- HI fused phenyl 3-yl ring 5-39 3,5-di-F-4o-CH,C(O)- -CH 3 R1R 3 -pyrid- HI fused phenyl 4-yl 5-40 3,5-di-F-0-CH 2 -CH, R 2 1R 3 -CH, 0 fused phenyl 5-41 3,5-di-F--o-CHC(O)- -CH 3 -0 R 3 1R 4
-CH
3
I
(trans) fused phenyl ring 5-42 3,5-di-F-,A-CHC(O)- -CH, -41 R 3
/R
4
-CH
3
I
(cis) fused phenyl ring 5-3 3,5-di-F--CH,C(Q)- -CH, R4 3 /R 4
I
(trans) fused phenyl ring WO 98/28268 PCTIUS97/22986 112-- TABLE 6-1
H
Ex.[ RI R2 W R3 Q 6-1 3,5-di-F-0-CHC(O)- j-CH, -CH, H H 6-2 3,5-di-F-0k-CH 2 j-CH, -CHCH, H F 6-16 3,5-di-F-0-CHC(O)- -CH, H c H TABLE 6-2 R' n R-W2 R, 6-3 3,5-di-F-0-CH,C(O)- 0 -CH,CH, -CH 3
-CH,
6-4 3.S-di-F-0-CH,C(O)- 1 -CH 3 H H H 3.5-di-F-40-CH,C(O)- 1 -CH, -CH2t0 H WO 98t28268 PTU9128 PCT/US97/22986 113 R7 ~R 3 R" 6-6 cyclopentyl-CH 2 0 -CH 2 CH, -CH 3
-CH
3 6-7 3,5-di-F-0-CH 2 1 -CH 3
-CH
3 H H 6-8 3,5-di-F-0-CH 2 0 -CH, -CH, -CH 3
H
6-9 3,5-di-F-0-CHC(O)- I -CH 3 -CH, -CH, H 6-13 3,5-di-F-0-CHC(O)- I -CH 3 H -CH 3
-CH
3 6-14 3,5-di-F-0-CHC(Q)- I -CH, -CH, -CH, -CH 3 6-15 3.5-di-F-46CH(OH)C(O)- 1 *CH 3 -CH, -CH, -CH, 6-17 t3,S-di-F-4-CH,C(O)- 1 -CH, -CHCH, -CH, -CH, TABLE 6-3 Ex. R1R2 J 6-10 3,5-di-F-40-CH 2
-CH
3
-CH
3 0 6-11 3,5-di-F-40-CH 2
-CH
3
-CHCH
3 0 6-12 3,5-di-F-0-CHC(0)- -CH,
!C
3 j WO 98t28268 WO 9828268PCT/US97/22986 114-- TABLE 7-1
H
Ex. T R I R' 1 1 RxI1W77 7-1 3,5-di-F0 -CH, -CH, H H H CHC(O)- 7-2 3,5-di-F-0- -CH, -CH 3 H H H
CH(QH)C(O)-
7-3 3,5-di-F-0- -CH, -CH 3 H H H
C(O)C(O)-
7-4 3,5-di-F-0- -CH(CH 3 2 -CH, H H H
CH,C(O)-
3 ,5-di-F-0- -C(CH 3 3
-CH
3 H H H CHC(O)- 7-6 3.5-di-F-0- -CH 3 H H H CH(OH)C(O) 7-7 3,5-di-F-0- -C(CH 3 3
-CH
3 H H H CH(OH)C(O) 7-8 3,5-di-F-4o- -CH 3 -CHC(Q)OCH, H H H CHC(O)- 7-9 3,5-di-F-0- -CH, -CH,C(Q)OH H H H CH,C(O) 7-10 3,5-di-F-40- -CH, -CH,C(O)C(CH) 3 H H H CHC(O)- 7-11 3,5-di-F-0- -CH, -CH 2 H H H CHC(O)- morpholin-4-yi 7-12 (CH 3 2 CH- -CH 3
-CH
3 H H H CH(QH)C(O) 7-13 cyclopentyl- -CH(CH 3 -CH, H H H CH(OH)C(O) 7-14 (CH 3 3 -CH, -CH 3 H H H CH(OH)C(O) I_ WO 98/28268 PCT/US97/22986 115 Ex. R' I R 2 7J7, 7-15 cyclopentyl- -C(CH 3 3
-CH
3 H H H CH(OH)C(O) 7-16 cyclopentyl- -CH 3 CH, H H H
CH(OH)C(O)-
7-17 3,5-di-F-46- -CH 3 H H H H
CH
2 7-18 3,5-di-F-0- -CH, -CH,CH(CH), H H H CHC(O)- 7-19 (CH 3
-CH
3 H H H CH(OH)C(O) 7-20 -CH 3
-CH
3 H H H CH(OH)C(Q) 7-21 -CH, H H H 7-22 4-0 -CH, -CH, H H H furazan-3-yi 7-24 3,5-di-F-40- -CH, -(CHZ)40 H H H CHC(O)- 7-25 3,5-di-F-0- -CH 3
-CH
2 -cyclopropyl H H H CHC(O)- 7-26 3,5-di-F-0- -CH, -CHCF, H H H CH,C(O) 7-27 3,5-di-F-0- -CH 3 cyclohexyl H H H CHC(O)- 7-28 3,5-di-F-0- -CH 3 -CH, F H H CH(OH)C(O) 7-29 3,5-di-F-0- -CH 3 -CH, H H F CH(OH)C(O) 7-30 3,5-di-F-0- -CH 3 -CH, H F H CH(OH)C(O)- 7-31 3,5-di-F-40- -CH 3
-CH
2 -CYClopropyl H H H CH(OH)C(O) 7-32 3,5-d-F-0t- -CH 3
-(CH
2 )40 H H H CH(OH)C(O) 7-33 3,5-di-F-0- -CH(CH 3 2 -CH,-Cyclopropyl H H H CH(OH)C(O) 7-34 3,5-di-F-0- -(CH 2 )40 H H H CH(OH)C(O) 7-35 3,5-di-F-4i- -CH(CH 3 hexyl H H H CH(OH)C(O)- 7-36 3,5-di-F-40- -CH(CH 3 2 -CH, H F H I I CH(QH)C(O) WO 98/28268 PCTIUS97t22986 116-- [Ex. R' RI R 2Xizil7 7-37 3,5-di-F0 -CH, H H F CH(QH)C(O)- 7-38 3,5-di-F-S- -CH, F H H CH(OH)C(O) 7-39 3,4-di-CI-0- -c1 -CH 3 H H IH TABLE 7-2
H
117 TABLE 7C-1I 0 0 WO 98/28268 PTU9128 PCTIUS97t22986 118-- Ex. R' R2 7C-22 CH 3
(CH,)
3 -CH, -CH, 7C-23 thien-2-yi-CH 2 -CH, -CH, 7C-24 thien-2-yI-(CH 2 3 -CH, -CH, 7C-25 4-N0 2 -qS-(CH 2 3 -CH, -CH, 7C-26 2,4-di-F-0-CHC(Q)- -CH 3
-CH
3 7C-27 2.6-di-F-4i-CH 2 -CH, -CHI 7C-28 4-(CH,),CH-0-CHC(O)-
-CH
3
-CH
3 7C-29 adamantan-1-yi-CH 2
-CH
3
-CH,
7C-30 cyclohexyl-(CH 2 4 -CH, -CH, 7C-3 1 CHSCHC(O)- -CH, -CH, 7C-32 thien-2-yI-(CH 2 4 -CH, -CH, 7C-33 norbornan-2-yI-CH 2 -CH, -CH, 7C-34 3 ,5-di-F-0-CH,C(O)- -CH 2
CH(CH,CH
32
-CH,
7C-35 3 ,5-di-F--4-CH 2
-CH,CH(CH
3
)CH
2
CH
3
-CH
3 7C-36 3,5-di-F-.0-CHC(O)- -CH 2 -CYClopropyl -CH 3 7C-37 3,5-di-F-4i-CH 2
-CHCH
2 -CYClohexyl -CH, 7C-38 3,S-di-F-4,-CHC(O)- -(C1 2 5 CH,F -CH, 7C-39 3,5-di-F-4,-CH 2
-CH,CH(CH
3
)CHCH
3
-CH
3 7C-40 cyclohexyl-CH 2 -CH,CH(CH,CH), -CH, 7C-41 cyclopropyl-CH 2
-CH
3
CH(CHCH
3 2
-CH
3 7C-42 (CH 3 2 CHCHC(O)- -CH 2
CH(CH
2
C
3 2
-CH
3 7C-43 3-CF 3 +4$CHC(O)- -C,CH(CH,CH 3 2
-CH
3 7C-44 3,4-di-F-0-CHC(O)- -CHCH(CH 2
CH)
2
-CH,
7C-45 2,4-di-F-0-CH 2
-CHC(CHCH
3 2
-CH,
7C-46 3-F-0-CH,C(Q)- *CH,CH(CH,)CHCH, -CH, 7C-47 cyclopentyl-CH 2
-CHCH(CH
3 )CH2CH 3
-CH,
7C-48 cyclohexyI-CHC(O)- -CH,CH(C 3
)CHCH
3
-CH
3 7C-49 cyclopropyl-CH 2
-CH
2
C(CH
3 )CHCH, -CH 3 7C-50 thien-2-yi-CH 2 -CH2CH(CH 3
)C,CH
3
-CH
3 7C-51 (CH,)ICHCHC(O)- -CHCH(CH,)CH,CH, -CH, 7C-52 3-CF,-4O-CHC(Q)- -CH,C(CH,)C,CH 3
-CH
3 7C-53 4-F-0-CH 2
-CHCH(CH
3 )CH,CH, -CH 3 F7C-54 3,4-di-F-0-CH 2
-CH,C(CH
3
)CH,CH
3
-CH
3 WO 98t28268 PCT/US97/22986 119-- I Ex. R' [l R 2 7C-55 2,4-di-F-0-CHC(O)- -CH,CH(CH,)CHCH, -CH, 7C-56 3-F-0-CHC(O)- -CHCH 2 cyclohexyI -CH, 7C-57 cyclopentyl-CH 2
-CH
2 CHcyclohexyI -CH 3 7C-58 cyclohexyl-CH 2 -CHCH~cyclohexyI -CH, 7C-59 cyclopropyl-CH 2
-CH
2
CH
2 cyclohexyI -CH, 7C-60 (CHI) 2 CHCH,C(O)- -CH 2 CH,Cyclohexyl -CH, 7C-61 4-F-40-CH,C(O)- -CHICH 2 cyclohexyl -CH 3 7C-62 3,4-F--k-CH 2
-CH
2 CH~cyclohexyI -CH 3 7C-63 2,4-F-4,-Cll 2
-CHCH
2 CccohexyI -CH 3 7C-64 3-F-0-CHC(O)-
-(CH
2 5 CH-,F -CH 3 7C-65 cyclopentyl-CH 2
-(CH
2 5
CH
2 F -CH 3 7C-66 cyclohexyl-CH 2
-(CH
2 5
CH
2 F -CH 3 7C-67 cyclopropyl-CH 2 5
CH
2 F -CH, 7C-68 (CH 3 )2CHCHC(Q)- 5 CH,F -CH, 7C-69 3-CF 3 -O-CHC(O)- -(CH 2 ),CH,F -CH, 7C-70 4-F+-OCHC(O)- 5
CH
2 F -CH 3 7C-7 1 3 -(CH 2 5 CH,F -CH, 7C-72 2 ,4-F-0-CHC(Q)- H 2 5 CH,F -CH, 7C-73 4-CH,Q-O&CHC(O)- -CH 3
-CH,
7C-74 4-CH 3 O-0-CHCH 2 -CH, -CH, 7C-75 naphth-1-yi-CH 2 -CH, -CH, 7C-76 3,4-methylenedioxy-O-CHPCO)- -CH, -CH 3 7C-77 -0-CH 2
CH
2 -CH, -CH, 7C-78 CH 3
(CH
2 6 -CH, -CH, 7C-79 3-HO-4,-CH,CH,C(O)-
-CH
3
-CH
3 7C-80 4-CH 3 -0-CH,CH,C(O)- -CH, -CH, 7C-8 1 4-C 1-0-CH,CH,C(O)-
-CH
3
-CH
3 7C-82 CHCH(O)CH 2 -CH 3
-CH
3 7C-83 4-HO-0~-CH,CH 2 -CH, -CH, 7C-84 3.4 .5-tri-F-0-CH,C(O). -CH, -CH, 7C-85 4-CHQ-O-CH,CH,CH,C(O)-
-CH
3
-CH
3 7C-86 CH 3 OC(O)CHCH,C(O)- -CH, -CH 3 C-7 40-CH,CH,CH,C(O)-
-CH
3 -CHI 7 WO 98t28268 PCTIUS97/22986 120 [Ex. R 7C-88 O-CH,-S-CH,CH 2 -CHI -CH 3 7C-89 CHCH,CH(CH 3 )CHC(Q)- -CHI -CHI
CHOC(O)(CH,)
6 -CHI -CHI 7C-91I indan-2-yi-CHC(O)- -CHI -CHI 7C-92 CHOC(O)(CH,) 4 -CHI -CHI 7C-93 (2-methylbenzofuran-3-yI)CH 2 -CHI -CHI 7C-94 CH 3 CHC(O)- -CHI -CHI 7C-95 CH 3 OCH,CH,C(O)- -CHI -CHI 7C-96 4-F-0-CHCH 2 -CHI -CHI 7C-97 4-F-40-OCH,CHC(O)- -CHI -CHI 7C-99 CH 3
CH=CHCH
2 -CHI -CHI 7C-100 2,4-di-C-40-O-(CH 2 -CHI -CHI 7C-101 2,3-di-Cl-t0-O-CHC(Q)- -CHI 7C-102 4-CI-OC(Q)-CH 2 CH,C(O)- -CHI -CHI 7C- 103 4-F-0-NHC(O)CHCHC(O)- -CHI -CHI 7C-104 (-O),CHNHC(O)CHCHCHC(Q)- -CHI -CHI 7C-105 2-F-q0-CH 2 -CHI -CHI 7C-107 O-NHC(O)CH 2
CH
2 -CI -CHI 7C-108 2,4-di-CI-0-Q-CHC(O)- -CHI -CHI 7C-109 2-NO,-46-CH,-C(O)- -CHI -CHI 7C-1 10 CH,(CH,),CH(-O)CHC(O)- -CHI -CHI 7C-1 I11 -CHI -CHI 7C-112 2-F-3-CF,-4O-CHC(O)- -CHI -CHI 7C-1 13 2,4,6-tri-F-0-CH 2 -CHI -CHI 7C-1 14 4-F-2-CF 3 -0-CH 2 -CHI -CHI 7C-1 15 2-F-4-CF 3 -CHI -CHI 7C-1 16 4-HO--O-CH,C(O)- -CHI -CHI 7C-1 17 4-CH 3 O-4O-O-CH,C(O)- -CHI -CH 3 7C-1 18 2-CHO+OCH,C(O)- -CHI -CHI 7C-1 19 2-Br-.O-CH,C(Q)- -CHI -CHI 7C- 120 4-(O-CH,Q-)Ob-O-CH,C(O)- -CHI -CHI 7C- 11 4-HO-40-O-CH,C(O)- -CHI -CHI 7C-122 CHC(O)CHCH,C(O)- -CHI -CH 3 WO 98/28268 WO 9828268PCT/US97122986 121 Ex. R' l z 7C-123 2-HO-0-CH,C(O)- -CH, -CH, 7C-124 3.4-di-CHO-O-CHC(O)- -CH, -CH, 7C-125 4-CH 3 O-O(CO)-CH2CHC(O)- -CH, -CH, 7C-126 O(CO)-CH 2 CHC(O)- -CH, -CH 3 7C-127 3-HO-40-CHC(O)- -CH, -CH 3 7C-128 CH 3 C(Q)N(Oi)CH 2 -CH, -CH 3 7t-129 thien-3-yi-CH,C(O)- -CH, -CH, 7C-130 0-(CH 2 5
-CH
3
-CH,
7C-131 cyciohexyI-(CH 3 -CH, -CH, 7C-132 2,3,5--tri-F-r1-CH,C(O)- -Cli 3
-CH,
7C-133 2,4,5-tri-F-0-CH 2
-CH
3
-CH,_
7C-134 CH,=CHCH 2 -CH, -CH 3 7C-135 CH 3
S(CH
2
-CH
3
-CH,
7C-136 3-NQ,-O-CH,C(O)- -CH 3
-CH
3 7C-1 37 (CH 3 3 CNHC(O)CH,CH,C(O)- -CH, -CH 3 7C-138 4-Br-O-CH 2 -CH, -CH 3 7C-139 4-F-OC(O)-CH,CHC(O)- -CH 3
-CH
3 7C-140 2-CI-40-O-CHC(Q)- -CH 3
-CH
3 7C-141 4-CH 3
-CH
3
-CH,
7C-142 3-CH 3 -0-CH 2 -CH, -CH, 7C-143 3,4-di-CI-q0-CH,C(O)- -CH 3
-CH
3 7C-144 4-Ci-4-O-CHC(Q)- -CH 3
-CH
3 7C- 145 3-CH,--O-O-CHC(O)- -CH 3
-CH
3 7C-146 4-(CH 3 2
CH-O,-O-CH
2
-CH
3
-CH,
7C-147 -CH 3
-CH,
7C-148 OSCHC(O)- -CH, -CH 3 7C-149 4-C2,O-O-CH,C(O)- -CH 3
-CH,
7C-150 2,5-di-CH 3 O-0-CH,C(O)- -CH, -CH, 7C-151 2-CH,-O&CHC(O)- -CH, -CH 3 7C-152 (0),CHCH,C(O)- -CH, -CH, 7C-153 OQCH,CH,C(O)- -CH 3
-CH,
7C-154 4-CF,-O-CHC(Q)- -CH, -CH 3 7C-155 4-CH,-O-O-CH,C(O)- -CH, -CH, WO 98/2268 PCT/US97/22986 122-- I Ex. R' Il 7C-156 2-(46O)-O-CHC(O)- -CH3 -CH 3 7C-157 -CH, -CH 3 7C-158 3,4-di-CI-0-O-CHC(O)- -CH, -CH, 7C-159 4-F-q0-Q-CHC(O)- -CH, -CH 3 7C..160 3,4.5-tri-CH 3 O0i0-CH 2 -CH3 -CH 3 7C-162 thianaphthen-4-yi-CH 2
-CH
3
-CH
3 7C-163 CH 3 OCHC(O)- -CH, -CH, 7C-164 C,HOCH.,C(O)- -CH- 3
-CH,
7C-165 OOCHC(Q)- -CH, -CH, 7C-166 3-CH 3 O-O-O-CHC(O)-
-CH
3
-CH
3 7C-1 67 4-C 4
,H
9 -CH 3
-CH
3 7C-168 2-CH 3 O-0-CH 2 CHC(O)- -CH, -CH 3 7C-169 (CH 3 2
NC(O)CH
2 CH,C(O)- -CH 3
-CH
3 7C-170 3 ,4-methylenedioxy-&-CHCH 2
-CH
3
-CH
3 7C- 171 2-C I-6-F-0-CH 2 -CH, -CH 3 7C-172 2,5-di-F-0-CH 2
-CH
3
-CH
3 7C- 173 2,3,4,5 ,6-penta-F-40-O-CH 2
-CH
3
-CH,
7C-174 3,5-di-CF-4O-CHC(O)- -CH, -CH 3 7C-175 3,5-di-CH 3 -0-O-CHC(O)- -CH 3
-CH
3 7C-1 76 4-Cl-o-CH 2
-CH
3
-CH,
7C- 177 3-CI-0-O-CHPCO)- -CH, -CHI 7C-178 benzo[b]thien-3-yI-CH 2 -CH, -CH, 7C-179 3,5-di-CHO-O-CH 2
-CH
3
-CH,
7C-180 2.5-di-CH,-4O-CHC(O)-
CH
3
-CH,
7C-181 2,4.6-tri-CH 3 -CH 3
-CH
3 7C- 182
-CH
3
-CH,
7C- 183 (CH 3 3
COC(O)NH(CH
2 2
-CH-
3
-CH,
7C-184 trans-styryl-CH,C(O)- -CH, -CH, 7C-185 H2NC(O)(CH,),C(Q)-
-CM
3
-CH
3 7C- 186 2-CI-o-CH,CH,C(O)- -CM 3
-CH,
7C-187 CH 3 CH,CH-,C(O)- -CH, 7 -CH, WO W828268 PCT/US97/22986 123 Ex. J R 7C-188 CH 3
CH
2
CH=CHCH
2 -CH, -CH, 7C-189 o(CH 2 4 -CH, -CH, 7C-190 3-CHO-tO-CH,CH,C(O)-
-CH
3
-CH
3 7C-191 4-CI-0-CH(CH,)CHC(O)- -CH, -CH, 7C-192 CHCH(CF,)CH,C(O)- -CH, -CH, 7C-194 naphthalen-1-yi-O-CH 2 -CH, -CH 3 7C- 196 2-(CF 3 )-o-C(O)CH,CH 2 -CH, -CH, 7C- 197 OC(Q)NHCH(O)CH,CHC(O)- -CH, -CH, 7C-198 CH 3
CH(=NHOH)CH,CH
2 -CH, -CH 3 7C-199 4-CH,-O-NHC(Q)CHCH,CH,C(O)-
-CH
3
-CH
3 7C-200 4-(C,H,-4O-O)o-O-CHC(Q)-
-CH
3
-CH
3 7C-201 OC(O)CH(O)CH,CH 2
-CH
3
-CH,
7C-202 4-(HOCH,)-,O-O-CH 2
-CH
3
-CH
3 7C-203 CF 3
(CH
2 2 -CH, -CH 3 7C-204 (CH 3 2 CHC(Q)NHCH(0)CHC(O)- -CH- 3
-CH,
7C-205 2-CH,-O-O-CH 2
-CH
3
-CH
3 7C-206 OSO 2
CH
2 CHC(O)- -CH, -CH 3 7C-207 4-NO 2 -CH, -CH 3 7C-208 C,OCH,CH,C(Q)- -CH 3
-CH,
7C-209 2,3-di-F-0-CH(OH)C(Q)- -CH, -CH, 7C-210 2,6-di-F-0-CH(OH)C(O)- -CH, -CH 3 7C-211I 4-F-0-CH(OH)C(O)- -CH, -CH, 7C-212 2,5-di-F-43-CH(OH)C(O)-
-CH
3
-CH
3 7C-2 13 45-CH,CH(OH)C(O)-
-CU
3
-CH
3 7C-2 14 O-CH(OH)C(O)- -CH, -CH, 7C-215 4-CI-(6CH(OH)C(O)- -CH, -CH, 7C-216 (CH,)2CHCH,CH(OH)C(O)- -CH, -CH, 7C-217 4-Br-qS-CH(OH)C(O)- -CH, -CH, 7C-218 CHICH(QH)C(O)-
-CH
3
-CH
3 7C-219 -bCH,CH(OH)C(O)- -CH 3
-CH,
7C-220 (CH 3 )2CHCH,CH,CH,C(O)- -CH, -CH, 7-C221 3.5-di-F-40-CH,C(O)- -CHCHSCH, -CH, WO 98/2868 PCT/US97I22986 124-- Ex.I R' R R 2 7-C222 3,5-di-F-0-CH,C(O)- -0 -CH 3 7-C223 3.5-di-F-0-CHC(Q)- -CHCH(CH,), -CH, 7-C224 3,5-di-F-0-CH 2 cyclohexyl -CH, 7-C225 3,5-di-F-0-CHC(O)- -CH(OH)CH, -CH, 7-C226 3,5-di-F-40-CHC(Q)- thien-2-yI -CH, 7-C227 thien-2-yi-CH 2
-CH
2 CHSCH, -CH, 7-C228 thien-2-yi-CH,C(Q)- -0 -CH, 7-C229 thien-2-yI-CH 2 -CHCH(CH,), -CH, 7-C230 thien-2-yI-CH 2 cyclohexyl -CH 3 7-C231 thien-2-yI-CH 2 -CH(OH)CH, -CH, 7-C232 thien-2-yi-CH2C(O)- thien-2-yi -CH,_ 7-C233 (CH 3 2
CHCH
2
-CH
2
CH
2
SCH
3
-CH
3 7-C234 (CH 3 2
CHCH
2
-CH,
7-C235 (CH 3 2
CHCH
2
-CHCH(CH
3 2
-CH,
7-C236 (CH 3 )2CHCH 2 cyclohexyl -CH, 7-C237 (CHI) 2
CHCH
2 -CH(OH)CH, -CH, 7-C238 (CH 3 2 CHCHC(O)- thien-2-yi -CH, 7-C239 O-CH 2
-CH
2 CH,SCH, -CH3 7-C240 4i-CH 2 -0 -CH, 7-C241 4-CH 2 -CHCH(CH,), -CH 3 7-C242 O-CH 2 cyclohexyl -CH, 7-C243 4O-CH 2
-CH(OH)CH-
3
-CH,
7-C244 -0-CH 2 thien-2-yI -CH 3 WO 98/28268 PCTIUS97/22986 125 TABLE 8-1
R
2 =1 position; RI 5 position; R" 7 position IEx.I R R' I X'iXI R' R 2 R R 3 JR-In 8-1 3,5-di-F-0- HH CH, -0 H 0 8-2 3,54+4F-- H H H -CH, -CHCH, -0 H 1 8-3 3,5-di-F-0- H H H -CH 3 H -0 H 1 8-4 3,5-di-F-0- H HH -CH, -CH3 piperidin- H I -yI 3.5-di-F-0- H H,H -CH 3 -CH, -0 cI 1 8-6 3,5-di-F-iO- H H,H -CH 3 -CH, 2-F-0- Br 1 8-7 3,5-di-F-45- -CH 3 H.H -CH 3
-CH
3 1 8-8 3,5-di-F-0- H H,H -CH3 -CH 3 2-CI-q0- CI I 8-9 3,5-di-F-0- H H,H -CH 3 -CH, cyclohexyl H 1 8-10 3,5-di-F-0- H H,H -CH 3
-CH
3 -0 NO, 1 8-11 3,5-di-F-t0- H H,H -CH 3
-CH
3 H 1 8-12 3,5-di-F-0- H OH,H -CH(CH 3 2
-CH
3 -46 H 1 8-13 3,5-di-F-0- H OH,H -C(CH 3 3
-CH
3 -0 H 1 8-14 3,5-di-F-40- H H,H -CH 3 -CH, H 1 8-15 3,5-di-F-S- H H.H -CH, -CH 3 4-F-0- H I 8-16 cyclopentyl H OH.H -CH 3
-CH
3 -0 H I 8-17 cyclopenryl H OH,H -CH(CH,) 2 -CH, -0 H 1 8-8 3,5-di-F-S- H H.H -CH 3
-CH
3 -CH, H I WO 98/28268 PCTUS97/22986 126-- E.R J R XIYX R' R2 R~ in 8-19 3,5-di-F-46- H H,H -CH, CH,CH(CH,), -0 H 1 8-20 3,5-di-F-0- H OH,H -CH, -CH, -0 H I 8-21 3,5-di-F--o- H =0 -CH, -CH 3 H 1 8-22 CH 3 S- H H.H -CH 3 -CH, H 1 8-23 3,5-di-F-0- H H,H -CH(CHp 2 -CH, -0 H 1 8-24 3,5-di-F-0- H H,H -C(CH 3 3
-CH
3 -0 H I 8-25 3,5-di-F-0- H H,H -CH, -0 H 1 8-26 3,5-di-F-0- H H,H -CH, 1-cyclopropyl- H I _____methyl 8-27 3,S-di-F-0- H F.H -CH 3
-CH
3 -46 H 1 8-28 3,5-di-F-0- H H,H -CH 3
-CH,CHCH
3 -0 H I 8-29 H H,H -0 -CH 3 -0 H 1 8-30 3,5-di-F-0- H H,H -0 -CH 3 -0 H I 8-31 O-S- H H.H -CH, -CH 3 -10 H I 8-32 (CH 3 )ICH- H H,H -CH 3 -CH, H 1 8-33 4-S- H H,H -0 -CH, -0 H 1 8-34 4-CH 3 H H,H -CH 3
-CH
3 0 H I CH,- 8-35 3-Br-4b- H H,H -CH, -CH 3 -45 H 8-36 cyclohexyl- H H,H -CH, -CH 3 -0 H 1 8-37 4-CH 3 0-0- H H,H -CH 3 -CH3 2-pyridyl H 1 8-38 (CH 3 H OH,H -CH 3
-CH
3 H 1 8-39 (CH 3 2 CH- H OHH -CH(CH 3 2
-CH
3 -ct H. I 8-40 (CH 3 3 C- H OH,H -CH, -CH 3 -0 H 1 8-41 2-thienyl H H,H -CH, -CH, 2-pyridyl H 1 8-42 3,5-di-F-0- H H,H -CH 3 -CH, 2-pyridyl H 1 8-43 3-Br-4o- H H,H -CH 3
-CH
3 2-pyridyl H 1 8-44 O-S- H H.H -CH, -CH, 2-pyridyl H 1 8-45 4-CHiCH 2 O+0 H H,H -CH, -CH, 2-pyridyl H 1 8-46 4-CF 3 H H,H -CH 3
-CH
3 2-pyridyl H 1 8-47 3,5-di-CF 3 H H.H -CH 3 -CH, 2-pyridyl H 1 8-8 CHS- H H.H -CH3 -CH 3 2-pyridyl H I 8-9 cyclohexyl H H,H: -CH 3 -CH, 2-pyridyl H I WO 98/28268 PCT/US97/22986 127-- Ex. I R x'/x"I R R3__ R4 n 8-50 2,3,4,5,6- H H,H -CH 3 -CH, 2-pyridyl H I penta-F-0-O- 8-51 3-thio- H H,H CH 3 -CH, 2-pyridyl H 1 naphthalyl 8-52. 2,4,6-tri- H H,H -CH 3 -CH, 2-pyridyl H I H H. -H 3 -CC -piyl H 8-54 H H,H -CH 3
-CH
3 2-pyridyl H 1 8-55 2-thienyl- H H,H -CH 3
-CH
3 2-pyridyl H I CH,CH, 8-56 (CH 3 2 CH- H H.H -CH 3 -CH, 2-pyridyl H 1 8-57 CHOC(O)CH,- H H,H -CH, -CH, 2-pyridyl H 1 8-60 2,6-di-F-0- H OH,H -CH 3 -CH, 2-pyridyl H I 8-61 4-F-0- H 01,H -CH, -CH 3 2-pyridyl H 1 8-62 2.5-di-F-0- H QH,H -CH 3
-CH
3 2-pyridyl H 1 8-63 2,4,6-tri-F-0- H H.H -CH 3
-CH
3 2-pyridyl H 1 8-64 2-CF 3 H H,H -CH 3 -CH, 2-pyridyl H 1 8-65 CFCH,- H H,H -CH 3
-CH
3 2-pyridyl H I 8-66 (4-(CH3) 2 CH-) H H,H -CH 3
-CH
3 2-pyridyl H 1 8-6 HH -H -l -yiy 8-68 H OH.H -CH, -CH 3 2-pyridyl H I 8-69 47CI-0- H QH,H -CH 3
-CH
3 2-pyridyl H I 8-70 (CH 3 H H,H -CH, -CH 3 2-pyridyl H 1 8-71 2,3,5-trj-F-0- H H,H -CH 3
-CH
3 2-pyridyl H I 8-72 CH 3 S-CH,- H H,H -CH 3
-CH
3 2-pyridyl H 1 8-73 (CH,)2CH- H QHH -CH, -CH, 2-pyridyl H 1 8-74 3-NQ,-O- H H,H -CH 3 -CH, 2-pyridyl H 1 8-75 4-CH 3 0-0- H H,H -CH 3
(CH
3 3 CC(0)- 2-pyridyl H 1 8-76 2-thienyl H H,H -CH, (CH 3 3 CC(0)- 2-pyridyl H I 8-77 3,5-di-F-0- H HH -CH 3
(CHI)
3 CC(0)- 2-pyridyl H I
CH,-
8-78 3-Br-o- H H,H -CH 3
(CH
3 3 CC(O)- 2-pyridyl H I I I CH,- WO 98/28268 PTU9128 PCTIUS97t22986 128-- IEx.[ R R' R R 2 R 3 [R47n 8-79 H H,H -CH, (CH 3 3 CC(O)- 2-pyridyl H I
CH,-
8-80 4-CHCH 2 H H,H -CH, (CH 3 3 CC(O)- 2-pyridyl H 1
CH
2 8-81 4-CF 3 H H.H -CH 3
(CH
3 3 CC(Q)- 2-pyridyl H 1
CH,-
8-82 3,5-di-CF 3 H H,H -CH 3
(CH
3 2-pyridyl H I
CH,-
8-83 CHS- H H,H -CH 3 2-pyridyl H I 8-84 cyclohexyl H H,H -CH, (CH 3 3 CC(O)- 2-pyridyl H I 8-85 2,3,4,5,6- H H,H -CH, (CH 3 3 CC(O)- 2-pyridyl H I penta-F-4)-O- 8-86 3-ti- H H,H -CH, (CH 3 3 CC(Q)- 2-pyridyl H 1 naphthalyl CH,- 8-87 2,4,6-tri-CH 3 H H,H -CH, (CH 3 3 CC(O)- 2-pyridyl H 1 8-88 H H,H -CH 3
(CH
3 3 CC(O)- 2-pyridyl H I
CH
2 8-89 3,4-di-F-4)- H H.H -CH 3
(CH
3 3 CC(O)- 2-pyridyl H 1 8-90 thien-2-yi- H H,H -CH 3
(CH
3 3 CC(O)- 2-pyridyl H I CHCHV. CH,- 8-91 (CH 3 2
CH(CH
2 2 H H,H -CH 3
(CH
3 3 CC(O)- 2-pyridyl H 1 8-92 CH 3
OC(O)CH
2 H H,H -CH, (CH 3 3 CC(Q)- 2-pyridyl H I
___CH
2 8-95 2,6-di-F-4)- H OH,H -CH, (CH 3 3 CC(O)- 2-pyridyl H I
CH
2 8-96 H QH,H -CH, (CH 3 3 CC(O)- 2-pyridyl H 1
CH,-
8-97 2,5-di-F-4)- H 01,H -CH 3
(CH
3 3 CC(O)- 2-pyridyl H I 8-98 2,4,6-tri-F-4)- H H,H -CH 3
(CH
3 3 CC(Q)- 2-pyridyl H I
CH,-
8-99 2-CF 3 H H,H -CH 3 2-pyridyl H 1
CH,-
8-100 CF 3 CH,- H H,H -CH 3
(CH
3 3 CC(O)- 2-pyridyl H I I I CH, 8-101 H H,H -CH 3
(CH
3 3 CC(0)- 2-pyridyl H 1 CH,- WO 98128268 PCT[US97t22986 129-- 8-102 -OCH,- H OH,H -CH, 2-pyridyl H I
CH,-
8-103 0- H OH,H -CH, (CH 3 2-pyridyl H 1
CH,-
8-104 4-CI-0- H H,H -CH, (CH3)ICC(O)- 2-pyridyl H I
CH,-
8-105 (CH 3 H H,H -CH, (CH 3 3 CC(O)- 2-pyridyl H 1 CHr_ 8-106 2,3,5-tri-F-0- H H,H -CH 3 2-pyridyl H 1
CH,-
8-107 CH 3
S-CH
2 H H,H -CH, (CH,) 3 CC(Q)- 2-pyridyl H 1 CH,- 8-108 H OHH -CH, (CH 3 3 CC(O)- 2-pyridyl H I CH,- 8-109 3-NO 2 H H,H -CH, (CH 3 3 CC(O)- 2-pyridyl H 1
CH
2 8-110 4-CH 3 O-0& H H,H -CH 3
(CH
3
CH
2 2 N- 2-pyridyl H 1
CH
2
CH
2 8-111 2-thienyl H H.H -CH, (CH 3
CH,-)
2 N- 2-pyridyl H I CHCH,- 8-112 3,5-di-F-0- H H,H -CH, (CH 3 2-pyridyl H I CHCH,- 8-113 3-Br-tk- H H,H -CH, (CH 3
CH
2 2 N- 2-pyridyl H 1
CH,CH,-
8-114 O-S- H H,H -CH 3
(CH
3 CH,N- 2-pyridyl H 1
CHCH
2 8-115 (4-CH 3 CHQ)-o- H H,H -CH, (CH 3 2-pyridyl H I 8-116 CH 3 S- H H,H -CH, (CH 3
CH
2 2 N- 2-pyridyl H 1 ~CHCH,- 8-117 cyclohexyl H H,H -CH, (CH3CH,),N- 2-pyridyl H 1 8-118 2,3,4,5.6- H H,H -CH, (CH3CH,),N- 2-pyridyl H I penta-F-0-O- 8-119 3-thio- H H,H -CH, (CHCH,)2N- 2-pyridyl H 1 naphthalyl ___CHCH,- 8-120 0- H =0 -CH, (CHCH,),N- 2-pyridyl H I 8-121 2,4,6-tri-CH,- H H,H -CH, (CHCH,N- 2-pyridyl H I 0_ CH,CH 2 8-122 H H.H -CH, (CHCH,)2N- 2-pyridyl H I CHCH,- WO 98/28268 PCTIUS97/22996 130-- R JX'IX" j R' R2 J R3 nj 8-123 3,4-di-F-0- H HH -CH, (CHCH,),N- 2-pyridyl H 1 8-124 thien-2-yi- H H,H -CH 3 (CHCH,),N- 2-pyridyl H I CHCH,- CH,CH,- 8-125 H H,H -CH, (CH 3
CH
2 N- 2-pyridyl H I CH,CH,- 8-126 CH 3
OC(O)CH
2 H H,H CH 3
(CHCH
2 N- 2-pyridyl H I
CHCH,-
8-129 H OH,H -CH, (CH 3 2-pyridyl H 1 8-130 4-F-0- H OH,H -CH 3
(CH
3
CH
2 2 N- 2-pyridyl H I
CH,CH,-
8-131 2,5-di-F-0- H OH.H -CH 3
(CH
3
CH
2 2-pyridyl H I
CHCH
2 8-132 4-HOCH 2 H H,H -CH 3
(CH
3
CH
2 2-pyridyl H I
CH,CH
2 8-133 2,4,6-tri-F-0~- H H,H -CH, (CH 3
CH
2 2-pyridyl H I
CHCH
2 8-134 2-CF 3 H H,H -CH 3
(CH
3
CH,
2 N- 2-pyridyl H 1
CHCH
2 8-135 CF 3 CH,- H H,H -CH, (CH 3
CH
2 2 N- 2-pyridyl H I
CHCH,-
8-136 (CH,),CH-46- H H,H -CH, (CH 3
CH
2 2-pyridyl H I
CH
2 CH,- 8-137 r$CH,- H OH,H -CH 3
(CHCH
2 2 N- 2-pyridyl H I
CH,CH
2 8-138 0-H OH,H -CH 3
(CHCH,)
2 N- 2-pyridy) H I I_ CHCH,- 8-139 4-CI-0- H OH,H -CH, (CH3CH 2 2 N- 2-pyridyl H I
CH,CH,-
8-166 3,5-di-F-0,- H H,H -CH,
-CH
3 H~ I WO 98/28268 PCTIUS97/22986 131 TABLE 8-2 R' =1I position; R 3 5 position; RI 7 position Ex. R X'X' -IJ R~ J I R I 3R'JnJ 8-140 3,5-di-F-0- OH,H H thien-3- -CHC(CH), -CH 2
C(CH
3 3 H I 8-141 3.5-di-F--4- OH,H H -CH 3 -0 -CH, H I 8-142 3.5-di-F-0- OH,H H -CH, -CH, -0 H I 8-146 3.5-di-F-4,- H,H H -CH 3 -CH(CH), H 1 8-147 3,5-di-F-0- H,H H 2-thienyl -CH(CH), -CH(CH 3 H I 8-148 CYCIOPrOPYl H,H H 2-thienyl -CH(CH 3 )2 H 1 8-149 cyclopentyl H.H H 2-thienyl -CH(CHO,2 H I 8-150 3,5-di-F-0- H,H H -CH 3
-CH
3 -CH, H 1 8-151 3,5-di-F-46- OH,H H -CH- 3 -CH, -CH, H I 8-152 3,5-di-F-40- H,H H -CH, -CH 2
CH(CH)
2
-CH,CH(CH
3 2 H I 8-153 cyclopentyl. H,H H -CH, -CH,CH(CH), -CH,CH(CH 3 2 H 1 8-154 cyclopropyl H,H H -CH, -CHCH(CH 3 2
-CHCH(CH
3 2 H I 8-155 3,5-di-F-0- H,H H -CH,CH(CH) -CH,CH(CH,)2 H I 8-156 3,5-di-F-0- H,H H -CH, 1-cyclopropyl- 1-cyclopropyl- H I methyl 8-157 cyclopentyl H,H H -CH, 1-cyclopropyl- 1-cyclopropyl- H I methyl 8-158 cyclopentyl OH,H H -CH, 1-cyclopropyl- 1-cyclopropyl- H I methyl methyl 8-159 3.5-di-F-0- H,H H -CH, -CH,C(CH 3 3
-CH,C(CH)
3 H I 810 3,5-di-F-0- OH.Hl H -CH 3
-CH,C(CH
3 3
-CHC(CH
3 3 H I II WO 9=/8268 PCT1UJS97/22986 132 8461 R JI/jl RJ R' R 8__161_ cyclopentyl H,H H -CH, -CH,C(CH 3 3 H 1 8-162 cyclopentyl OH.H H -CH 3
CH,C(CH
3 3 H 1 8-163 3,5-di-F-.0- H.H H -CH, -0 -0 H I 8-164 cyclopentyl H,H H -CH, -0 H 1] 8-165 cyclopentyl OHH H T -CH, -0 -0 H :1 TABLE 8-3 x xv 0
R
N
R
HN N n 0
N
R2=I position; R 3 5 position; R 4 7 position WO 98/28268 P~r[US97/22986 133 TABLE 8-4 XA"
B
X ,H
N
R
0 [Ex. I R R' J RR W A-B 8-143 3,5-di-F-- {HH -CH, -0 -CH= CH- 8-144 3,5di-F-0 jHH -CH, -0 -CH 2
-CH
2 8-145 3,5di-F-- jHH -CH, -0 -N=CH- TABLE R yNN 0 H
N
Ex. R X/l R 2 8-167 3.5-di-F-0- H,OH -CH, -CH, WO 98/28268 C1S9128 PCT/US97/22986 134 TABLE 8C-1 0
N-
HI 0
R
2 1 position; RI 5 position; R 4 7 position [R X R 2 Il 3_R4 _SO 3.4-methylenedioxy-o- H,H -CH3 -CH 3 -0 H R,S 2-CH,0-45-O- H.H -CH 3 -CH, -0 H R,S 4+(CH 3 )2CH]0-O- H.H -CH, -CH 3 -0 H R,S
CH
3
CH
2 O- H.H -CH 3 -CH, -0 H R,S H,H -CH 3 -CH, H R,S 4-CH 3 CH,0-0& H,H -CH 3
-CH
3 -0 H R,S 3 0-0& H,H -CH, -CH 3 -0 H R,S 3,5-di-F-0- 1,11 -CH 3 -CH, -0 H R,S 2-CH,-4i- H,H -CH, -CH 3 -0 H R,S (0) 2 CH- 1,11 -CH 3 -CH, -0 H R,S H,H -Cl 3
-CH
3 -0 H R.S indol-3-yi- 11,11 -CH 3 -CH, -43 H R,S 4-CF 3 -43- H.H -CH, -CH, -43 H R,S 4-CH,-43-O- H.H -CH 3
-CH
3 -43 H R,S 4-HOCH,-- 1-,H -CH 3 -CH, -43 H RS 2-(03-0-)03- H .H -CH, -CH, -43 H R, WO 98/28268 PCT/US97/22986 135 and I (at* 3o--q H.H -CH, -CH, -0 H R,S 3.4-di-CI-0-O- H,H -CH 3 -CH, -0 H R,S
-CH
3 -CH, H R,S
CH
3 S- H,H -CH 3 -CH, H R,S
CH
3 O- H,H *-CH 3 -CH, -46 H R.S
-CH
3 -CH, -41 H S 4-H,H -CH 3 -CH, -0 H S 4'-CHCH,- H,H -CH, -CH 3 H S 3-CH 3 H,H -CH, -CH, -0 H S 4-(n-C4H1 9 0)46-O- H,H -CH, -CH, -45 H S 2-CH 3 H,H -CH 3
-CH
3 -41 H S
-CH
3 -CH, 4 H S H,I -CH 3
-CH
3 H S H,H -CH 3
-CH
3 H S 3-(3.4-methylene- H,H -Cl 3
-CH
3 H S dioxy)4'-CH,- cyclopentyl-CH,- H,H -CH 3
-CH
3 H S cyclopenten-2-yi- H,H -CH 3
-CH
3 H S 2-F-6-0I4- H.H -CH 3 -CH, H S cyclohexyl- H,H -CH 3
-CH
3 H S 2.5-di-F-4'- I,H -CH 3 -CH, -0 H S 2,3,4.5,6-penta-F-4'-O- H,H -CH 3
-CH
3 H S HH -CH 3 -CH, -0 H S 4-CI-4' H,l -CH, -CH 3 -0 H S 3-CI-4'-0- H,H -CH, -CH 3 -0 H S benzofb]thiophen-3-yl H,I -CH, -CH 3 H S
-CH
3 -CH, H S 3.5-di-CH,0-4'- H,I -CH 3 -CH, H S 2.54d-CH 3 H.I -CH 3 -CH, H S 2.6-di-F-4'- H.H -CH 3
-CH
3 H S 2,4-di-F-4'- H,H -CH, -CH 3 H S mesityl HH -CH 3
-CH,
3 S WO 98/28268 PCT1US97t22986 136 R XJ R R 2 J R 3 IV SO H,H -CH, -CH, -0 H S 3,4-di-F-0- H,H -CH, -CH, -0 H S trans-styryl H,H -CH, -CH, -0 H S tk-C(O)CH,- H,H -CH, -CH, -0 H S
CH
3
CH
2 CH=CH- H,H -CH, -CH, H S (trans)
CHCH,CH,CH
2 CH,- H.H -CH 3 -CH, 0 H S 4-CH 3 -4'-CH 2 H,H -CH, -CH 3 -0 H S 4-CI-4'-CH 2 H,H -CH, -CH 3 -0 H S
CH
3 CH(q5)- H,H -CH, -CH, H S 4-CHO-4'-CHCH,- H.H -CH, -CH, -0 H S CHOC(O)CH,- H,H -CH, -CH, -0 H S 4'-CHCH,- H,H -CH 3 -CH, H S 4'CHSCH,- HH -CH, -CH 3 -0 H S
CH
3
CH
2 CH(CH,)- H,H -CH, -CH, -0 H S
CHCHCH
2
CH
2
CH
2 H,H -CH 3 -CH3 H S indan-2-yI H.H -CH 3 -CH, -0 H S 4-CH 3 H.H -CH 3
-CH
3 -0 H S 2-CI-4'-O- H,H -CH 3
-CH
3 H S 2-thienyl H,H -CH 3 -CH, -41 H S 2-CF 3 H,H -CH, -CH 3 -0 H S 4-CH 3 -40- H,H -Cl 3 -CH, -0 H S 2,6-di-F-4'- 11,01- -CH3 -CH, -0 H S 4-CH,04'-CH,- I.H -CH 3 -CH, H S 3,5-di-F-4'- H,H -CH 3 -CH, -0 H S 3-CH 3 1,H -CH 3 -CH, H S H,H -CH, -CH 3 H S 4-CI-4'-O- H.H -CH, -CH 3 H S 2-naphthyl H,H -CH, -CH 3 H s 3-CI-4'- H.H -CH, -CH, H S 3-CH 3 -04'-O H,H -Cl 3 -CH, H S WO 98/28268 PCT/US97/22986 137 R X R' R 2
R
3 1R4 Iso.
an (ate 3,4-methylenedioxy-0- H.H -CH, -Cf! 3 -0 H S 2-CH 3 O-0-O- H.H -CH, -CH, -0 H S 4-[(CH 3 )2CH]4)-O- H,H -CH 3 -CH, -0 H S
-CH,
3 -CH, -0 H S 4--H,H -CH 3 -CH, H S 4-CH 3 CH,O-4)- H.H -CH, -CH 3 -0 H S 2.5-di-CH,0-4)- H,H -Cf! 3 -0 H S H,H -CH 3 -46 H S 2 Cf!- H,f! -CH, H S H,H -Cf! 3
-CH
3 -0 H S indol-3-yi- H,H -CH 3 -Cf! 3 -0 H S H,H -CH, -0 H S 3 f!,H -Cf![ 3 -Cf! 3 -0 H S 2-00)- Hf -CH 3 -Cf! 3 -0 H S f!,H -Cf! 3 -Cf! 3 -0 H S H,f! -Cf! 3 -Cf! 3 -41 H S 2,4-di-CI-4)- H,H -Cf! 3 -Cf! 3 -0 H S
CH
3 S- H.H -Cf! 3 -CH, -0 H S 4---H,QH -Cf! 3
-CH,
3 -0 H S 4-thionaphthenyl H.H -CH, -Cf! 3 -0 H S CHI0- H,H -Cf! 3 -Cf! 3 -0 H S
CH
3 Cf! 2 0- H,H -Cf! 3 -Cf! 3 -41 H S 2-CI-46-CH,- H,H -Cf! 3
-CH
3 -0 H S CHCH,- H.H -Cf! 3 -Cf! 3 -0 H S
CH
3 CH,CH,CH,- H.H -Cf! 3 -Cf! 3 -0 H S 4)CH,CH,CH,- H.H -Cf! -CH 3 -0 H S thien-2-yi-CH,Cf!,- f!,f -Cf! 3 H S 3-CHO-4)-CH,- f!.f -Cf! 3 -Cf! 3 -40 H S (CH,)2CHCH2CH,- f!,H -Cf! 3 -Cf! 3 H S EHf! -Cf! 3 -Cf! 3 H S
CH
3 -Cf! 3 -Cf! 3 H S WO 98/28268 PCTIUS97/22986 138 R X R R 3 R4 IO and(a 3-HO-40-CH 2 H.H -CH, -CH, -0 H S 4-H-10--CH, H.H -CH, -CH, H S 3.4.5-CF 3 H,H -CH 3
-CH
3 -0 H S cyclopentyl H,H -CH 3
-CH
3 -0 H S
CH
3 CH- H.H -CH, -CH 3 -0 H s 2-CH 3 -benzofuran-3-yI H,H -CH, -CH, -41 H S
CH
3 H,H -CH 3
-CH
3 -0 H S cyclopropyl HH -CH 3
-CH
3 -0 H s CHOCH,- HH -CH 3
-CH
3 -0 H S thienyl-CH 2 CHCH,- H,H -CH, -CH 3 H S 2 H,H -CH 3
-CH
3 -0 H S H,H -CH, -CH, -0 H S norbornan-2-yI H,H -CH 3
-CH
3 -0 H S 2,3-di-F-.k- H,OH -CH 3 -CH, -0 H S
CH
3 CH=CH- H,H -CH, -CH, -41 H S 2,4-di-CI-40-O- H,H -CH, -CH 3 -0 H S
CH
2 CH,- 2,3-di-CI-0-O- H.H -CH, -CH 3 -40 H S H,H -CH, *CH 3 -0 H S 2 H,H *CH3 -CH 3 -0 H S 4-HOCH,-4,-O- H,H -CH 3 -CH, -0 H S 2-F-3-CF 3 -40- H,H -CH 3 -CH, -0 H S 2,4,6-tr-CF 3 H,11 -CH, -CH 3 H S 4-F-2-CF 3 H,H -CH 3
-CH
3 -0 H S CFC11 2 H,H -CH, -CH, H S 2-F-4-CF 3 H,H -CH 3
-CH
3 H S 4-Br-4)- H,H -CH 3
-CH
3 H S H,H -CH, *CH 3 H S 2-CH 3 H,H -CH 3 -CH, H S 4-CH 3 O-45-O- H.H -CH, -CH 3 H S 4)SO,CH,- H.H -CH 3 -CH, H S WO 98/28268 PCTIUS97/22986 139 and (at 2-CH 3 O+0 H.H -CH, -CH, -0 H s 2-Br-4'- H,H -CH, -CH, H S 4-[(CH,)2CH]45- H.H -CH, -CH 3 -0 H S CH,=CHCH,- H,H -CH, -CH, -0 H S 4-HO-4'-O- H,H -CH, -CH 3 -0 H S CHOCH,- HH -CH, -CH, -0 H S 2-HO-4'- H.H -CH, -CH, H s 3,4-di-CHO-4'- H,H -CH 3 -CH, -0 H S 4-CH 3 H,H -CH 3 -CH, -0 H S thien-3-yI H,H -CH 3 -CH, -0 H S 4CH,CH,CH,CH,- H,H -CH, -CH, -40 H S H,H -CH, -CH 3 H S 2,3,S-tri-F-46- H.H -CH 3 -CH, H S 2,4,5-tri-F-4'- H,H -CH, -CH3 -4 H S adamantan-1-yI H,H -CH 3 -CH, H S cyclohexyl- H,H -CH 3 -CH, H S CHCH,CH,- thien-2-yI H.H -CH, H S 3-CF 3 H,H -CH 3 H S 3,S-di-F-4'- H,H -CH, H S 3-CH 3 H,H -CH, H S H,H -CH 3 H S 3-Br-4'- H,H -CH, H S 3-CI-45 H,H -CH, H S 3,4-methylenedioxy-4o- H.H -CH3 H S H,H -CH, H S 3.5-di-CF,-4,- H,H -CH3 H S CH3S- H,H -CH, H S H.H -CH3 H S H,H CH 3 H S cyclohexyl H.H -CH, H S 2,5-di-F-45- H.H -CH, H S WO 98/28268 PCTIUS97/22986 140and (at).
benzollbJthiophen-3-yI H,H -0 -CH 3 H S =0 -CH, -0 H S 2,6-di-F-4,- H,H -0 -CH, H S 2,4-di-F-4,- H.H -46 -CH3 -0 H S 3.4-di-F-4,- H.H -0 -CH3 H S
CH
3 CH,- H,H -0 -CH3 H S
CH,(CH
2 4 I-,H -CH, H S thien-2-yi-CH,CH 2 H,H -0 -CH3 -0 H S (CH,)2CHCH,CH,- H,H -CH, -0 H S OH-H.H -0 -CH 3 H S cyclopentyl H,H -0 -CH 3 -0 H S
CH
3 H,H -0 -CH, H S 3,4,5-CF 3 H.H -0 -CH3 -0 H S 4)-CH2CH 2 H,H -0 -CH3 -0 H S 2-thienyl H,H -CH3 *CHCH,- H R,S ~CH2CF, 2-thienyl H,H -CH, -CII 2 C(0)4 -0 H R,S 2-thienyl H,H -CH, -CH 3 2-thiazolyl H R,S 2-thienyl H,H -CH, -CH3 -0 CI R.S 2-thienyl H.H -CH 3 -CH3 2-CI-4) CI R,S 2-thienyl H,H -CH, -CH, 2-thienyl H R,S 2-thienyl H,H -CH, -CH, cyclohexyl H R,S 2-thienyl H,H -CH 3 -CH3 Br R,S 3,5-di-F-4)- H,H -CH3 -CHCH,- H R,S 3 3,5-di-F-4)- H,H -CH, -CH,C(0)4) -0 H R,S 3.5-di-F-4)- H,H -CH 3
-CH
3 2-thiazolyl H R,S 3,5-di-F-4)- H.H -CH 3 -CH, -0 CI R.S 3,5-di-F-4)- H,H -CH 3 -CH, 2-CI-46- CI R,S 3.5-di-F0 H.H -CH, -CH 3 thien-2-yi H R,S 3.5-di-F-4)- H.H -CH3 -CH, -cyclohexyl H R,S 3.5-di-F-0 H.H -CH 3
-CH
3 Br R,S WO 9=/8268 PCr/US97122986 141 R XR R 3 R 4
I
and(t* -CH, -CHZCH 2 -0 H R.S 3 11-0 ,11 -CH, -CH,C(Q)0 -0 H R,S H,H -CH 3 -CH, 2-thiazolyl H R.S -CH, -CH, -qS CI R,S H,H -CH 3
-CH
3 2-CI-0- CI R,S
-CH
3 -CH, thien-2-yi H R.S H,H -CH 3
-CH
3 cyclohexyl H R,S H,H -CH 3 -CH, Br R,S CHS- H,H -CH, -CHCH,- -40 H R,S 3 CHS- H,H -CH, -C 2 C(O)45 -0 H R,S CHS- H,H -CH, -CH 3 2-thiazolyl H R.S
CH
3 S- H,H -CH 3
-CH
3 CI R,S
CH
3 S- H,H -CH 3
-CH
3 2-CI-0- CI R,S
CH
3 S- H,H -CH 3 -CH, 2-thienyl H R,S CHS- H,I -CH 3
-CH
3 cyclohexyl H R.S
CH
3 S- H,H -CH 3 -CH, Br R,S H,H -CH 3
-CI,CH
2 -0 H R,S
CHCF
3 H,I -CH 3
-CH
2 C(O)4) H R.S H,H -CH 3
-CH
3 2-thiazolyl H R,S H,H -CH, -CH, -0 CI R,S H,I -CH, -CH, 2-CI-4)- CI R,S H,H -CH, -CH, 2-thienyl H R,S H.I -CH 3 -CH, cyclohexyl H R,S =0 -CH, -CH 2
CI
2 H R,S
CH,CF,
=0 -CH 3 -CH;C(O)4) H R,S =0 -CH 3
-CH
3 2-thiazolyl H R,S =0 -CH 3
-CH
3 2-CI-4)- CI R,S -CH, -CH, 2-thienyl H R,S =0 -CH, -CH, cycloey H R,S WO 98/28268 PCTUS97t22986 142and(at =0 -CH, -CH 3 Br R,S
CH
3 CH,- H,H -CH, -CH 2 CH,- -0 H R,S 3 CHCH,- H,H -CH, -CH,C(0)o -0 H R.S
_CH
3 CH,- H,H -CH, -CH, 2-thiazolyl H R,S
CH
3 CH,- H.H -CH 3 -CH, CI R,S CHCH,- H,H -CH 3
-CH
3 2-CI-0- CI R,S CHCH,- H.H -CH 3
-CH
3 2-thienyl H R,S CHCH,- H.H -CH 3
-CH
3 cyclohexyl H R,S CHCH,- H,H -CH 3 -CH, Br R,S (2-thienyl)-CHCH 2 H,H -CH 3 -CHCH,- -0 H R,S CHCF, (2-thienyl)-CHCH,- H,H -CH 3 -CHC(Q)4) -0 H R,S (2-thienyl)-CH 2 CH,- H,H -CH, -CH, 2-thiazolyl H R,S (2-thienyl)-CH 2
CH
2 H.H -CH 3
-CH
3 -0 CI RS (2-thienyl)-CH 2 CH,- H,H -CH 3 -CH, 2-C0-4,- CI R,S (2-thienyl)-CH,CH,- H.H -CH 3 -CH, 2-thienyl H R.S (2-thienyl)-CH 2 CH,- H,H -CH, -CH, cyclohexyl H R,S (2-thienyl)-CH 2
CH
2 H,H -CH, -CH, Br R.S cyclopencyl HH -CH 3
-CH
2 CH,- -0 H R,S 2
CF
3 cyclopentyl H,H -CH, -CH 2 C(0)4) -0 H R,S cyclopentyl H,H -CH 3
-CH
3 2-thiazolyl H R,S cyclopentyl H.H -CH 3
-CH
3 Cl R,S cyclopentyl H,H -CHI -CH, 2-CI-4)- CI R,S cyclopentyl H.H -CH, -CH, 2-thienyl H R,S cyclopentyl H,H .,-CH 3 -CH, cyclohexyl H R,S cyclopentyl H,H -CH, -eH 3 Br R,S CHCH- H,H -CH 3 -CH,CH,- H R,S
CH
2
CF
3 E CH 3 CH- H,H -CH, H
R,S
CF
3 WO 98/28268 PCT/US97/22986 143-- R X R R' R 3 R 4- Is.
and I
CH
3 CH- H.H -CH, -CH, 2-thiazolyl H R,S CHCH- H,H -CH 3
-CH
3 CI R.S CHCH- HH -CH, -CH 3 2-CI-3 CI RS CHCH- H,H -CFI 3 -CH, 2-thienyl H R,S
CH
3 CH- H,I *CH 3
-CH
3 cyclohexyl H R,S CF I 3 I CHCH- H.H -CH 3 -CH, 2-F-03- Br R,S
CF
3 CH,- H,H -CH, -CHCH,- -0 H R,S
CHCF
3
CF
3 CH,- H,H -CH, -CH,C(O)3 H R,S
CF
3 CH,- H,H -CH 3
-CH
3 2-thiazolyl H R,S CFCH,- H,I -CH, -CH 3 -43 CI R,S
CF
3 CH,- 1.H -CH, -CH, 2-CI-43- C! RS
CF
3 CH,- H,H *CH 3
-CH
3 2-thienyl H R.S CzFCH,- Hl -CH 3 -CH, cyclohexyl H R,S CFCH,- I.H -CH, -CH, Br R.S
(CH
3 2 CH- HH -CH 3 -CHCH,- -3 H R,S 3
(CH
3 H,I -CH 3 -CH,C(O)3 -43 H R.S
(CH
3 I,H -CH, -CH 3 2-thiazolyl H R,S
(CH
3 )2CH- H.1 -CH, -CH, -43 CI R,S 1.1 -Cl 3
-CH
3 2-CI-43- CI R,S
(CH
3 )2CH- I,H -CH, -CH, 2-thienyl H R,S (CH,)zCH- H.1 -CH 3 -CH, cyclohexyl H R,S (CH,)2CH- I.H -CH, -CH, 2-F-03- Br R,S
(CH
3 )zCHCH 2 H.OH -CH 3 -CH,CH,- -43 H R.S 3 WO 98/28268 PCTIUS97/22986 144-- R X RI R2 R 3 R 4
ISO.
and J (at (CH,)2CHCH,- H,OH -CH, -CH,C(O)4' -41 H R,S
(CH
3 2 CHCH,- H,QH -CH, -CH, 2-thiazolyl H R,S
(CH
3 )2CHCH,- H.QH -CH 3 -CH, -0 Cl R,S (CH3)2CHCH,- H,OH -CH, -CH, 2-CI-4'- Cl R,S
(CH
3 2 CHCH,- H,QH -CH 3 -CH, 2-thienyl H R,S (CH,)CHCHr- H,QH -CH, -CH 3 cyclohexyl H R.S (CH,).,CHCH2r HQH -CH, -CH, Br R,S -46 H,OH -CH, -CHCH 2 H R.S
_____CHCF
3 H.OH -CH, -CH 2 C(O)4' H R,S H,OH -CH, -CH, 2-thiazolyl H R,S H,OH -CH, -CH, Cl R,S H,QH -CH 3
-CH
3 2-CI-4'- Cl R.S H,QH -CH 3
-CH
3 2-thienyl H R,S H,QH -CH, -CH, cyclohexyl H R.S -40 H,OH
-CH
3 -CH 2-F- Br
R,S
3.5-di-F-4'- H,H -CH 3 H R.S 3.5-di-F-4'- H,H -CH 3
-CH
2 4' H R.S 3,5-di-F-45- H,H -CH 3 4-t-butyl- H R,S
CH
2 4 3,5-di-F-4'- H,H -CH 3 -CHCH,- H R,S cyclohexyl 3,5-di-F-4'- H.H -CH 3 3,3-dimethyl- H R.S butyl 3,5-di-F-4'- H,H -CH 3
CH
3 OC(Q)- -40 H R,S 3,5-di-F-4'- H,H -CH 3 2-ethyl- H R,S butyl 3.5-di-F-4'- H,H -Cl 3 cyclohexyl- H R,S ~~methyl 3.5-di-F-4'- H,H -Cl 3 2-4'-ethyl- H R.S 3.5-di-F-4'- H,H -CH 3 3-4'-propyl- H R.S H,H -CH 3 -40 H R.S phthalimidyl) WO 98/28268 PCTrIUS97/22986 145 R x} R' R'2 R1' [so.
3,5-di-F-0- H,H -CH, 2-biphenyl- -40 H R.S 3,5-di-F-0- H,H -CH, 2-tetrahydro- -0 H R.S furanylmethyl 3.5-di-F-4)- H,H -CH 3 2-(I,4-benzo- -0 H R,S dioxanyl) ____methyl 3,5-di-F-4)- H,H -CH, 3-(5-chloro- H R,S benzolb]thien _______-yl)methyl 3,5-di-F-4)- H,H -CH 3 3,3-dimethyl- -0 H R,S 2-oxo-propyl 3.5-di-F-4)- H,H -CH 3 5-benzofuraz- H RS anylmethyl 3,5-di-F-4)- H,H -CH 3 -0 H R,S propyl 3,5-di-F-4)- H,H -CH, 6-(2-CF 3 -0 H R,S quinolinyl) methyl 3,5-di-F-.0- H,H -CH, 2-methylbutyl H R.S 3.5-di-F-.0- FIX -CH, ethyl -0 H R,S 3,5-di-F-4)- H,H -CH, 3-pyridyl- -40 H R.S 3,5-di-F-40- H,H -CH 3 2-oxo-2-(N- H R,S indolinyl)- 3,5-di-F-.0- H,H -CH 3 4-(3,5-di- -0 H R,S methylisoxazolyl) methyl 3.5-di-F-04- H.H -CH, 2-CH 3 O-ethyl -0 H R,S cyclopentyl H.H -CH 3 -CH,4) -0 H R.S cyclopentyl H,H -CH 3 (4-t-butyl-) -0 H R,S _I CH,4) cyclopentyl H,H -CH 3
-CHCH
2 H R,S cyclohexyl cyclopentyl H,H -CH 3 3.3-dimethyl- H R.S butyl cyclopentyl H.H I-CH, isopropyl L H R.S WO 98/28268 PCT/US97/22986 146-- [R x I R' R R2 I 3R IO I cyclopentyl H,H -CH, CHOC(O)- -0 H R.S cyclopentyl H,H -CH, 2-ethyl- -41 H R,S cyclopentyl H,H -CH3 cyclohexyl- H R,S _____methyl cyclopentyl H.H -CH, 2-4)-ethyl- H R,S cyclopentyl H,H -CH3 3-4)-propyl- -0 H R.S cyclopentyl H,H -CH 3 0 H R.S phthalimidyl) ______ethyl cyclopentyl H,H -CH, 2-biphenyl- H R,S methyl_ cyclopentyl H,H -CH 3 3-(5-chloro- H R,S benzofb~thien cyclopentyl H.H -CH3 3,3-dimethyl- -0 H R,S 2-oxo-butyl____ cyclopentyl H,H -CH 3 5-benzofijraz- -0 H R,S anylmethyl cyclopentyl H,H -CH3 H R,S cyclopentyl H.H -CH3 6-(2-CF 3 -0 H R,S quinolinyl) methyl cyclopentyl H.H -CH, cyclopropyl- H R,S methyl_ cyclopentyl H,H -CH 3 2-methyl- H R,S butyl____ cyclopentyl H,H -CH3 ethyl H R,S cyclopentyl H,H -CH 3 4-(3,5-di- H R,S methylisoxazolyl) ~meth yl cyclopentyl H,H -CH3 Propyl H R,S cyclopentyl H,H -CH, 2-CH,O-ethyl H R,S CF,CH,- H,H -CH3 -CH,4) H R,S
CF
3 CH,- H.H (4-t-butyl)- H R.S I_ CH,4) I I_ WO 98/28268 PCT[US97/22986 147 R X R I1R2 R 3 R4 ISO.1 CFCH,- H,H -CH, -CH,CH,- -0 H R,S cyclohexyl
CF
3
CH
2 H,H -CH, 3,3-dimethyl- -0 H R,S butyl
CFCH
2 H,H -CH 3 iSapropyl H R,S
CFCH
2 H.H -CH 3 CHOC(O)- -0 H R,S
CF
3 CH,- H,H -CH, 2-ethyl- H R,S ~butyl
CF
3
CH
2 H,H -CH 3 cyclohexyl- H R.S ~methyl CF,CH,- H,H -CH 3 3-4,-propyl- -0 H 11,S CFCH,- H,H -CH 3 2-biphenyl- -0 H R.S methyl
CF
3
CH
2 H,H -CH, 3-(5-chloro- -0 H R,S benzotb]thien -yI)methyl
CF
3 CH,- H,H -CH 3 3,3-dimethyl- -0 H R,S 2-oxo-butyl
CF
2
CH
2 H.H -CH, 5-benzofuraz- -0 H R,S anylmethyl
CF
3 CHI- H.H -CH 3 -0 H R,S ______propyl
CFCH
2 H,H -CH, -0 H R,S quinolinyl) ____methyl
CF
3 CH,- H,H -CH, cyclopropyl- -0 H R,S methyl
CF
1
CH
2 H.H -CH 3 2-methyl- H R,S butyl
CF
3 CH,- H,H -CH, ethyl -0 H R,S CFCH,- H,H -CH, 4-(3,5-di- -0 H R,S methylisoxazolyl) methyl
CF
3 CH,- H,H -CH, propyl H R.S
CF
3 CH,- H.H -CH 3 2-CH 3 O-ethyl H 11,5 N-pyrrolidinyl H.H -CH3 -CH 3 H R,S 2-CI-4,-Q- H.H -CH 3 -CH, H R.S WO 98/28268 WO 9828268PCTIUS97/22986 148-- R X R' R 2 R3 R4 IO and(a 2-thienyl H.H -CH, -CH, -0 H R.S 3-F--H,H -CH, -CH, -0 H R.S H,H -CH, -CH 3 -0 H R,S 4-CH 3 O-0-CH,- H,H -CH 3 -CH, -0 H R.S H,H -CH 3
-CH
3 -0 H R,S 3-CH 3 H,H -CH 3
-CH
3 -t0 H R,S -CH, -CH 3 -0 H R,S H,H -CH 3 -CH, -40 H R,S H,H -CH 3 -CH, -4i H R,S 2-naphthyl HH -CH 3 -CH, -q5 H R,S 3-CH 3 H,H -CH, -CH 3 -0 H R,S WO 98/28268 PCTIUS97/22986 149-- TABLE 8C-2
IR
3 x X H
N
R N R4K" 0 N RI 1 position; R 3 5 position; R 4 7 position R XiX' R' W 2
R
3 {R4 2-thienyl H,H -CH 3 2,2-di-CH 3 2,2-di- H R.S propyl CH 3 -propyl 3,S-di-F-4)- HH -CH, 2,2-di-CH 3 2,2-di- H R,S propyl CH 3 -propyl H,H -CH 3 2,2-di-CH,- 2,2-di- H R,S propyl CH,-propyl
CH
3 S- H,H -CH, 2,2-di-CH 3 2,2-di- H R.S propyl CH 3 -propyl HH -CH 3 2,2-di-CH,- 2,2-di- H R,S propyl CH 3 -propyl =0 -CH, 2,2-di-CH,- 2,2-di- H R,S propyl CH 3 -propyl CHCH,- H,H -CH 3 2,2-di-CH,- 2.2-di- H R,S CH,-propyl 2-thienyl-CH 3
CH
2 H,H -CH, 2,2-di-CH 3 2,2-di- H R,S propyl CH,-propyl cyclopentyl H,H -CH 3 2,2-di-CH 3 2.2-di- H R.S propyl CH 3 -propyl CHCH- H,H -CH 3 2,2-di-CH 3 2.2-di- H R.S Iprapyl
CH
3 -propyl CF,
I__
CFCH,- HH -CH 3 2,2-di-CH,- 2,2-di- H R,S propyl ICH 3 -propyl I
(CH
3 2 CH- HH -CH, 2,2-di-CH 3 propyl CH3-propyl
R,S
WO 98t28268 PCT/US97/22986 150 I1 1I I1 (at (CH,)zCHCH,- OH,H -CH 3 2.2-di-CH 3 2,2-di- IH R,S I propyl CH,-propyl- IOH,H -CH, 2,2-diCHr- 2,2-di j H R,S J propyl CH 1 -propyl WO 98/28268 PCTIUS97/22986 151 Also included within the scope of this invention are prodrugs of the compounds of formula I above including acylated forms of alcohols and thiols, aminals of one or more amines, and the like.
DETAILED DESCRIPTION OF THE INVENTION As above, this invention relates to compounds which inhibit 0-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease. However, prior to describing this invention in further detail, the following terms will first be defined.
Definitions The term "3-amyloid peptide" refers to a 39-43 amino acid peptide having a molecular weight of about 4.2 kD, which peptide is substantially homologous to the form of the protein described by Glenner, et al.
1 including mutations and post-translational modifications of the normal 0-amyloid peptide.
In whatever form, the 0-amyloid peptide is an approximate 39-43 amino acid fragment of a large membrane-spanning glycoprotein, referred to as the 3amyloid precursor protein (APP). Its 43-amino acid sequence is: 1 Asp Ala Glu Phe Arg His Asp Ser Gly Tyr 11 Glu Val His His Gin Lys Leu Val Phe Phe 21 Ala Glu Asp Val Gly Ser Asn Lys Gly Ala 31 Ile Ile Gly Leu Met Val Gly Gly Val Val 41 Ile Ala Thr (SEQ ID NO: 1) or a sequence which is substantially homologous thereto.
WO 98/28268 PCT/US97/22986 152 "Alkyl" refers to monovalent alkyl groups preferably having from 1 to carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, n-hexyl, and the like.
"Substituted alkyl" refers to an alkyl group, preferably of from 1 to carbon atoms, having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2 -alkyl, -SO2-substituted alkyl, -SO 2 -aryl,
-SO
2 -heteroaryl, and mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, monoand di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic.
"Alkylene" refers to divalent alkylene groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (-CH 2 ethylene (-CHCH 2 the propylene isomers -CH 2
CH
2
CH
2 and -CH(CH 3
)CH
2 and the like.
"Substituted alkylene" refers to an alkylene group, preferably of from 1 to 10 carbon atoms, having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, and mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- WO 98/28268 PCT/US97/22986 153and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic.
Additionally, such substituted alkylene groups include those where 2 substituents on the alkylene group are fused to form one or more cycloalkyl, aryl, heterocyclic or heteroaryl groups fused to the alkylene group. Preferably such fused cycloalkyl groups contain from 1 to 3 fused ring structures.
"Alkenylene" refers to divalent alkenylene groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms. This term is exemplified by groups such as ethenylene the propenylene isomers -CH 2 CH=CH- and -C(CH 3 and the like.
"Substituted alkenylene" refers to an alkenylene group, preferably of from 2 to 10 carbon atoms, having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, and mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, monoand di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic. Additionally, such substituted alkylene groups include those where 2 substituents on the alkylene group are fused to form one or more cycloalkyl, aryl, heterocyclic or heteroaryl groups fused to the alkylene group.
"Alkaryl" refers to -alkylene-aryl groups preferably having from 1 to 8 carbon atoms in the alkylene moiety and from 6 to 10 carbon atoms in the aryl moiety. Such alkaryl groups are exemplified by benzyl, phenethyl and the like.
WO 98/28268 PTU9128 PCT/US97/22986 154-- "Alkoxy" refers to the group "alkyl-O-". Preferred alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, I ,2-dimethylbutoxy, and the like.
"Substituted alkoxy" refers to the group "substituted alkyl-O-" where substituted alkyl is as defined above.
"Alkylalkoxy" refers to the group "-alkylene-O-alkyl" which includes by way of example, methylenemethoxy (-CH,OCH 3 ethylenemethoxy
(-CH,CH,OCH
3 n-propylene-iso-propoxy
(-CH-,CH
2
CH,OCH(CH
3 2 methylene-t-butoxy (-CH,-O-C(CH 3 3 and the like.
"Alkylthioalkoxy" refers to the group "-alkylene-S-alkyl" which includes by way of example, methylenethiomethoxy (-CH 2
SCH
3 ethylenethiomethoxy
CH
2
CH-,SCH
3 n-propylene-thio-iso-propoxy
(-CH
2 CH,CH,SCH(CH3)2), methylenethio-f-butoxy (-CH-,SC(CH 3 3 and the like.
"Alkenyl" refers to alkenyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least I and preferably from 1-2 sites of alkenyl unsaturation. Preferred alkenyl groups include ethenyl n-propenyl (-CH,CH= CH 2 iso-propenyl
(-C(CH
3 and the like.
"Substituted alkenyl" refers to an alkenyl group as defined above having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylaniino, acyloxy, amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -S0 2 -alkyl, S0,- substituted alkyl, -S0,-aryl, WO 98/28268 PCTfUS97/22986 155 -SO,-heteroaryl, and mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic.
"Alkynyl" refers to alkynyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkynyl unsaturation. Preferred alkynyl groups include ethynyl (-CH=CH 2 propargyl (-CH,C-CH) and the like.
"Substituted alkynyl" refers to an alkynyl group as defined above having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO,-alkyl, -SO,-substituted alkyl, -SO,-aryl, -SO,-heteroaryl, and mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic.
"Acyl" refers to the groups alkyl-C(O)-, substituted alkyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl-C(O)- and heterocyclic-C(O)- where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.
"Acylamino" refers to the group -C(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic WO 9828268 PCT/US97/22986 156 wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
"Aminoacyl" refers to the group -NRC(O)R where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
"Aminoacyloxy" refers to the group -NRC(O)OR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
"Acyloxy" refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, cycloalkyl-C(O)O-, aryl-C(O)O-, heteroaryl-C(O)O-, and heterocyclic-C(O)Owherein alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic are as defined herein.
"Aryl" refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring phenyl) or multiple condensed (fused) rings naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like.
Unless otherwise constrained by the definition for the aryl substituent, such aryl groups can optionally be substituted with from 1 to 5 substituents selected from the group consisting of acyloxy, 1 to 5 and preferably 1 to 3 substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heterocyclic, WO 98/28268 PCTIUS97/22986 157 aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO,-alkyl, -SO,-substituted alkyl, -SO,-aryl, -SO,-heteroaryl, trihalomethyl, mono- and di-alkylamino, mono- and di- (substituted alkyl)amino, mono- and di-arylamino, mono- and diheteroarylamino, mono- and di-heterocyclic amino, and unsymmetric disubstituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic, and the like. Preferred substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy.
"Aryloxy" refers to the group aryl-O- wherein the aryl group is as defined above including optionally substituted aryl groups as also defined above.
"Carboxyalkyl" refers to the group "-C(O)Oalkyl" where alkyl is as defined above.
"Cycloalkyl" refers to cyclic alkyl groups of from 3 to 12 carbon atoms having a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
"Substituted cycloalkyl" refers to cycloalkyl groups having from 1 to (preferably 1 to 3) substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like.
"Cycloalkenyl" refers to cyclic alkenyl groups of from 4 to 8 carbon atoms having a single cyclic ring and at least one point of internal unsaturation.
WO 98/28268 PCTIUS9t2986 158 Examples of suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl and the like.
"Substituted cycloalkenyl" refers to cycloalkenyl groups having from 1 to 5 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like.
"Halo" or "halogen" refers to fluoro, chloro, bromo and iodo and preferably is either fluoro or chloro.
"Heteroaryl" refers to an aromatic carbocyclic group of from 1 to carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring (if there is more than one ring).
Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with 1 to substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, aryloxy, halo, nitro, heteroaryl, thiol, thioalkoxy, substituted thioalkoxy, thioaryloxy, trihalomethyl and the like. Such heteroaryl groups can have a single ring pyridyl or furyl) or multiple condensed rings indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl and furyl.
"Heterocycle" or "heterocyclic" refers to a monovalent saturated or unsaturated group having a single ring or multiple condensed rings, from 1 to carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur or oxygen within the ring.
WO 98/28268 PCT/US97/22986 159 Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, aryloxy, halo, nitro, heteroaryl, thiol, thioalkoxy, substituted thioalkoxy, thioaryloxy, trihalomethyl, and the like. Such heterocyclic groups can have a single ring or multiple condensed rings.
Preferred heterocyclics include morpholino, piperidinyl, and the like.
Examples of nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like as well as N-alkoxy-nitrogen containing heterocycles.
"Oxyacylamino" refers to the group -OC(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
"Thiol" refers to the group -SH.
"Thioalkoxy" refers to the group -S-alkyl.
"Substituted thioalkoxy" refers to the group -S-substituted alkyl.
"Thioaryloxy" refers to the group aryl-S- wherein the aryl group is as defined above including optionally substituted aryl groups also defined above.
WO 98/28268 PCT/US97/22986 160 "Thioheteroaryloxy" refers to the group heteroaryl-S- wherein the heteroaryl group is as defined above including optionally substituted aryl groups as also defined above.
As to any of the above groups which contain 1 or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically nonfeasible.
"Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of a compound of Formula I which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like can be used as the pharmaceutically acceptable salt.
The term "protecting group" or "blocking group" refers to any group which when bound to one or more hydroxyl, amino or carboxyl groups of the compounds (including intermediates thereof such as the aminolactams, aminolactones, etc.) prevents reactions from occurring at these groups and which protecting group can be removed by conventional chemical or enzymatic steps to reestablish the hydroxyl, amino or carboxyl group. The particular removable blocking group employed is not critical and preferred removable hydroxyl blocking groups include conventional substituents such as allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidine, phenacyl, t-butyl-diphenylsilyl and any other group that can be introduced chemically onto a hydroxyl functionality and later selectively removed either by chemical or enzymatic methods in mild conditions compatible with the nature of the product.
WO 98/28268 WO 98/28268 PCT/US97/22986 161 Preferred removable amino blocking groups include conventional substituents such as t-butyoxycarbonyl (t-BOC), benzyloxycarbonyl (CBZ), and the like which can be removed by conventional conditions compatible with the nature of the product.
Preferred carboxyl protecting groups include esters such as methyl, ethyl, propyl, t-butyl etc. which can be removed by mild hydrolysis conditions compatible with the nature of the product.
Compound Preparation When n is one or two, the compounds of formula I are readily prepared by conventional amidation of a carboxyl acid as shown in reaction below where, for the sake of illustration, n is one: WO 98/28268 PCT/US97/22986 162 RIZ
-NHO
0
H
2
N-CH
W
fr% (Reaction 1) Ri1 Z NH m Wr
H
N-CH
C
X
wherein R 2 W, X, Z and m are as defined above. The reaction is conventionally conducted by using at least a stoichiometric amount of carboxylic acid 1 and amine 2. This reaction is conventionally conducted for peptide synthesis and synthetic methods used therein can also be employed to prepare compound 3 which is a compound of formula I above. For example, well known coupling reagents such as carbodiimides with or without the use of well known additives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, WO 98/28268 PCT/US97/22986 163 etc. can be used to facilitate coupling. The reaction is conventionally conducted in an inert aprotic polar diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like. Alternatively, the acid halide of compound 1 can be employed in reaction and, when so employed, it is typically employed in the presence of a suitable base to scavenge the acid generated during the reaction. Suitable bases include, by way of example, triethylamine, diisopropylethylamine, N-methylmorpholine and the like.
When n is zero, the compounds of formula I can be prepared by Nsubstitution reactions of compound 2. For example, when m 0 and n 0, N-arylation reactions on compound 2 lead to compounds of formula I. When m 1 and n 0, reaction of compound 2 with an acetic acid derivative represented by the formula R'-T-CH 2 -COOH also lead to compounds of formula I. Both reactions are described below.
Synthesis of Carboxylic Acid Starting materials Carboxylic acids 1 can be prepared by several divergent synthetic routes with the particular route selected relative to the ease of compound preparation, commercial availability of starting materials, whether m is zero or one, whether n is one or two, etc.
A. Synthesis of Carboxylic Acids When m is zero and n is one, a first synthetic method involves the introduction of the R' group to the amino acid NH 2
CH(R
2 )COOH or ester thereof.
The introduction of the R' group onto the amino acid NH 2
CH(R
2
)COOH
or ester thereof can be accomplished in several methods. For example, conventional coupling of a halo acetic acid with a primary amine forms an amino acid as shown in reaction below: WO 98/28268 PCT/US97/22986 164--
H
Z' OH Ri-NH,
R
1 OH r
R
2 R2 4 5 6 (Reaction 2) wherein R' and R 2 are as defined above and Z' is a halo group such as chloro or bromo. Alternatively, leaving groups other than halo may be employed such as triflate and the like. Additionally, suitable esters of 4 may be employed in this reaction.
As above, reaction involves coupling of a suitable haloacetic acid derivative 4 with a primary amine 5 under conditions which provide for amino acid 6. This reaction is described by, for example, Yates, et al.1 4 and proceeds by combining approximately stoichiometric equivalents of haloacetic acid 4 with primary amine 5 in a suitable inert diluent such as water, dimethylsulfoxide (DMSO) and the like. The reaction employs an excess of a suitable base such as sodium bicarbonate, sodium hydroxide, etc. to scavenge the acid generated by the reaction. The reaction is preferably conducted at from about 25"C to about 100°C until reaction completion which typically occurs within 1 to about 24 hours. This reaction is further described in U.S. Patent No. 3,598,859, which is incorporated herein by reference in its entirety. Upon reaction completion, N-substituted amino acid 6 is recovered by conventional methods including precipitation, chromatography, filtration and the like.
WO 98/28268 PCT/US97/22986 165 In reaction each of the reagents (haloacetic acid 4, primary amine and alcohol 6) are well known in the art with a plurality of each being commercially available.
In an alternative embodiment, the R' group can be coupled to an alanine ester (or other suitable amino acid ester) by conventional N-arylation. For example, a stoichiometric equivalent or slight excess of the amino acid ester can be dissolved in a suitable diluent such as DMSO and coupled with a halo-R' compound, where Z' is a halo group such as chloro or bromo and R' is as defined above. The reaction is conducted in the presence of an excess of base such as sodium hydroxide to scavenge the acid generated by the reaction.
The reaction typically proceeds at from 15 C to about 250 0 C and is complete in about 1 to 24 hours. Upon reaction completion, N-substituted amino acid ester is recovered by conventional methods including chromatography, filtration and the like. This ester is then hydrolyzed by conventional methods to provide for carboxylic acid 1 for use in reaction In still another alternative embodiment, the esterified amino acids of formula I above can be prepared by reductive amination of a suitable pyruvate ester in the manner illustrated in reaction below: 0
R
2 fH Catalyst R R-NH2 H R1 OR Ca R 2 (Reaction 3) 7 5 8 WO 98/28268 PCTIUS97/22986 166 wherein R is typically an alkyl group and R' and R 2 are as defined above.
In reaction approximately stoichiometric equivalents of pyruvate ester 7 and amine 5 are combined in an inert diluent such as methanol, ethanol and the like and the reaction solution treated under conditions which provide for imine formation (not shown). The imine formed is then reduced under conventional conditions by a suitable reducing agent such as sodium cyanoborohydride, H 2 /palladium on carbon and the like to form the /N-substituted amino acid ester 8. In a particularly preferred embodiment, the reducing agent is H 2 /palladium on carbon which is incorporated into the initial reaction medium which permits imine reduction in situ in a one pot procedure to provide for the N-substituted amino acid ester 8.
The reaction is preferably conducted at from about 20*C to about 80 0
C
at a pressure of from 1 to 10 atmospheres until reaction completion which typically occurs within 1 to about 24 hours. Upon reaction completion, Nsubstituted amino acid ester 8 is recovered by conventional methods including chromatography, filtration and the like.
Subsequent hydrolysis of the ester 8 leads to the corresponding carboxylic acid derivative 1 which can be employed in reaction above.
For compounds where m is zero and n is two, conventional coupling of a second amino acid NH 2
CH(R
2 )C(O)OR where R is typically an alkyl group) to the amino acid produced above R'NHCH(R 2 )COOH) provides for esters of an analogue of carboxylic acid 1 which are then conventionally deesterified to provide for an analogue of compound 1.
Alternatively, an ester such as H2NCH(R 2
)C(O)NHCH(R
2 )COOR where each R 2 is independently as defined above and R is typically an alkyl group can first be formed by conventional peptide synthetic procedures, N-substitution can WO 98/28268 PCT/US97/22986 167 be conducted in the manner described above followed by de-esterification to provide for analogues of carboxylic acids 1 where n is two.
When m is one and n is one, a first synthetic method involves conventional coupling of an acetic acid derivative with a primary amine of an esterified amino acid as shown in reaction below:
'OR
R1 9 10 R2 (Reaction 4) X
X
1 1
O
R1
OR
R
2 wherein R is typically an alkyl group and R 2 X' and X" are as defined above.
Reaction merely involves coupling of a suitable acetic acid derivative 9 with the primary amine of amino acid ester 10 under conditions which provide for the N-acetyl derivative 11. This reaction is conventionally conducted for peptide synthesis and synthetic methods used therein can also be employed to prepare the N-acetyl amino acid esters 11 of this invention. For WO 98/28268 PCT/US97/22986 168 example, well known coupling reagents such as carbodiimides with or without the use of well known additives such as N-hydroxysuccinimide, 1hydroxybenzotriazole, etc. can be used to facilitate coupling. The reaction is conventionally conducted in an inert aprotic polar diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like. Alternatively, the acid halide of compound 9 can be employed in reaction and, when so employed, it is typically employed in the presence of a suitable base to scavenge the acid generated during the reaction. Suitable bases include, by way of example, triethylamine, diisopropylethylamine, Nmethylmorpholine and the like.
Reaction is preferably conducted at from about 0°C to about until reaction completion which typically occurs within 1 to about 24 hours.
Upon reaction completion, N-acetyl amino acid ester 11 is recovered by conventional methods including precipitation, chromatography, filtration and the like or alternatively is hydrolyzed to the corresponding acid without purification and/or isolation other than conventional work-up aqueous extraction, etc.).
In reaction each of the reagents (acetic acid derivative 9 and amino acid ester 10) are well known in the art with a plurality of each being commercially available.
When m is one and n is two, a further amino acid ester is coupled to the amino acid ester 11 by first de-esterifying 11 and then using well known peptide coupling chemistry with well known coupling reagents such as carbodiimides with or without the use of well known additives such as Nhydroxysuccinimide, 1-hydroxybenzotriazole, etc. which can be used to facilitate coupling. The reaction is conventionally conducted in an inert aprotic polar diluent such as dimethylformamide, dichloromethane, chloroform, WO 98/28268 PCT/US97/22986 169 acetonitrile, tetrahydrofuran and the like. De-esterification of the resulting ester provides for carboxylic acids 1 having n equal to 2.
Alternatively, carboxylic acids 1 having n equal to 2 can be prepared by first forming the ester, N-acetylating these esters and then de-esterifying the resulting product.
Carboxylic acids 1 having m equal to 1 and n equal to 1 or 2 can also be prepared by use of polymer supported forms of carbodiimide peptide coupling reagents. A polymer supported form of EDC, for example, has been described (Tetrahedron Letters, 34(48), 7685 (1993)) t0 Additionally, a new carbodiimide coupling reagent, PEPC, and its corresponding polymer supported forms have been discovered and are very useful for the preparation of such compounds.
Polymers suitable for use in making a polymer supported coupling reagent are either commercially available or may be prepared by methods well known to the artisan skilled in the polymer arts. A suitable polymer must possess pendant sidechains bearing moieties reactive with the terminal amine of the carbodiimide. Such reactive moieties include chloro, bromo, iodo and methanesulfonyl. Preferably, the reactive moiety is a chloromethyl group.
Additionally, the polymer's backbone must be inert to both the carbodiimide and reaction conditions under which the ultimate polymer bound coupling reagents will be used.
Certain hydroxymethylated resins may be converted into chloromethylated resins useful for the preparation of polymer supported coupling reagents. Examples of these hydroxylated resins include the 4-hydroxymethylphenylacetamidomethyl resin (Pam Resin) and 4benzyloxybenzyl alcohol resin (Wang Resin) available from Advanced Chemtech of Louisville, Kentucky, USA (see Advanced Chemtech 1993-1994 catalog, page 115). The hydroxymethyl groups of these resins may be WO 98/28268 PCT/US97/22986 170 converted into the desired chloromethyl groups by any of a number of methods well known to the skilled artisan.
Preferred resins are the chloromethylated styrene/divinylbenzene resins because of their ready commercial availability. As the name suggests, these resins are already chloromethylated and require no chemical modification prior to use. These resins are commercially known as Merrifield's resins and are available from Aldrich Chemical Company of Milwaukee, Wisconsin, USA (see Aldrich 1994-1995 catalog, page 899). Methods for the preparation of PEPC and its polymer supported forms are outlined in the following scheme.
NCO O
N
00 N
LG
Functionalized Resin where an inert polymer and LG CI. Br, I or OSOzCH 3 N N=C =N WO 98/28268 PCTUS97/22986 171 Such methods are described more fully in U.S. Patent Application Serial No. 60/019,790 filed June 14, 1996 which application is incorporated herein by reference in its entirety. Briefly, PEPC is prepared by first reacting ethyl isocyanate with 1-(3-aminopropyl)pyrrolidine. The resulting urea is treated with 4-toluenesulfonyl chloride to provide PEPC. The polymer supported form is prepared by reaction of PEPC with an appropriate resin under standard conditions to give the desired reagent.
The carboxylic acid coupling reactions employing these reagents are performed at about ambient to about 45 0 C, for from about 3 to 120 hours.
Typically, the product may be isolated by washing the reaction with CHCl 3 and concentrating the remaining organics under reduced pressure. As discussed supra, isolation of products from reactions where a polymer bound reagent has been used is greatly simplified, requiring only filtration of the reaction mixture and then concentration of the filtrate under reduced pressure.
Preparation of Cyclic Amino Compounds Cyclic amino compounds 2 employed in reaction above are generally aminolactams, aminolactones, aminothiolactones and aminocycloalkyl compounds which can be represented by the formula:
H
2
N-CH
X
where X is as defined above, Q is preferably selected from the group consisting of NR 6 and CRR where each of R 6
R
7 and R' are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl WO 98/28268 PCT/US97/22986 172 and heterocyclic with the proviso that if Q is or NR 6 then X is oxo or dihydro, and W" together with Q, C=X and CH forms a lactone, thiolactone, lactam, cyclic ketone, cyclic alcohol, a heterocycle, and the like.
The aminolactams, aminolactones and aminothiolactones of the formula above can be prepared by use or adaptation of known chemical syntheses which syntheses are well described in the literature. See, Ogliaruso and Wolfe, Synthesis ofLactones and Lactams, Patai, et al. Editor, J. Wiley Sons, New York, New York, USA, pp. 1085 et seq. (1993) 5 Specifically, 3-amino substituted lactams 13 with 5, 6 or 7 ring atoms may be prepared by the direct cyclization of a suitable alpha, omega-diamino acid ester 12 as shown in reaction below:
H
2 N-L- R I_ NH-Pr NH-Pr (Reaction 12 .1 wherein L is a linking group (typically an alkylene group) of from 2-4 atoms, Pr is a suitable protecting group such as t-butoxycarbonyl, carbobenzyloxy, or the like and R 9 is an alkoxy or aryloxy group such as methoxy, ethoxy, p-nitrophenoxy, N-succinimidoxy, and the like. The reaction may be carried out in a solvent such as water, methanol, ethanol, pyridine, and the like. Such reactions are exemplified by cyclization of a lysine ester to a caprolactam as described by Ugi, et al., Tetrahedron, 52(35):11657-11664 (1996) 1 6 Alternatively, such a cyclization can also be conducted in the presence of dehydrating agents such as alumina or silica to form lactams as described by Blade-Font, Tetrahedron Lett., 21:2443 (1980) 1 7 WO 98/28268 PCT/US97/22986 173 The preparation of aminolactams alkylated on the amino group of the cyclic lactam is described by Freidinger, et al., J. Org. Chem., 47:104-109 (1982) 1 8 and illustrated in reaction below:
LH
H
2
N
HI 6
Y
o 1. Reductive amination 2. Cyclization
O
-0 L (Reaction 6) NH-Pr MWFr wherein L and R 6 are as defined above.
In reaction reductive amination of 14 with aldehyde 15 and subsequent ring closure by methods using, for example, EDC provides for aminolactam 16. The preparation of 6 membered lactams using this general procedure is described by Semple, et al., J. Med. Chem., 39:4531-4536 (1996) 1 9 The internal cyclization of an amide anion with a halide or equivalent thereof can sometimes be used to particular advantage in the synthesis of smaller ring lactams where the stereochemistry of the amino-lactam center is available from the standard amino-acid pool. This approach is illustrated in reaction below: SMe BcHN' (Reaction 7) 0 17 WO 98/28268 PCT/US97/22986 174 where R 6 is as defined above.
The approach of reaction is presented by Semple, et al., supra.
1 9 and Freidinger, et al., J. Org. Chem., 47:104-109 (1982)18 where a dimethylsulfonium leaving group is generated from methyl iodide treatment of an alkyl methyl sulfide 17 to provide for lactam 18. A similar approach using a Mitsunobu reaction on an omega alcohol is found Holladay, et al., J. Org.
Chem., 56:3900-3905 (1991) 20 In another method, lactams 20 can be prepared from cyclic ketones 19 using either the well known Beckmann rearrangement Donaruma, et al., Organic Reactions, 11:1-156 (1960))21 or the well known Schmidt reaction (Wolff, Organic Reactions, 3:307-336 (1946)) 22 as shown in reaction below: Beckman rearrangement or
H
L Schmidt reaction L-N (Reaction 8) =0 (Reaction 8) 12 2 o wherein L is as defined above.
Application of these two reactions leads to a wide variety of lactams especially lactams having two hydrogen atoms on the carbon alpha to the lactam carbonyl which lactams form a preferred group of lactams in the synthesis of the compounds of formula I above. In these reactions, the L group can be highly variable including, for example, alkylene, substituted alkylene and hetero containing alkylene with the proviso that a heteroatom is not adjacent to the carbonyl group of compound 19. Additionally, the Beckmann rearrangement WO 98/28268 PCT/US97/22986 175 can be applied to bicyclic ketones as described in Krow, et al., J. Org. Chem., 61:5574-5580 19 9 6 2 The preparation of lactones can be similarly conducted using peracids in a Baeyer-Villiger reaction on ketones. Alternatively, thiolactones can be prepared by cyclization of an omega -SH group to a carboxylic acid and thiolactams can be prepared by conversion of the oxo group to the thiooxo group by P 2 S, or by use of the commercially available Lawesson's Reagent, Tetrahedron, 35:2433 (1979) 24 One recently reported route for lactam synthesis is a variation of the Schmidt reaction through the use of an alkyl azide, either intermolecularly or intramolecularly, through a tethered alkylazide function that attacks a ketone under acidic conditions. Gracias, et al., J. Am. Chem. Soc., 117:8047-8048 (1995)" describes the intermolecular version whereas Milligan, et al., J. Am.
Chem. Soc., 117:10449-10459 (1995) 2 6 describes the intramolecular version.
One example of the intramolecular version is illustrated in reaction below: 0 0 0
N
3 -am_
NP
0 10 (Reaction 9)
R.
o 21 where R 0 is exemplified by alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, heteroaryl, cycloalkyl and heterocyclic.
WO 98/28268 PCT/US97/22986 176 In this reaction, ketone 21 is converted to an a-(w-alkyl)ketone 22 which is cyclized to form bicyclic lactam 23. Such intramolecular reactions are useful in forming bicyclic lactams having 5-7 members and the lactam ring of 6-13 members. The use of hetero atoms at non-reactive sites in these rings is feasible in preparing heterobicyclic lactams.
Still another recent approach to the synthesis of lactams is described by Miller, et al., J. Am. Chem. Soc., 118:9606-9614 (1996) 27 and references cited and is illustrated in reaction (10) below: Pr N N HN N
H
2 N N 1 Pr O
O
2 r 2& where R 6 and Pr are as defined above and R" is exemplified by halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, heteroaryl, cycloalkyl and heterocyclic wherein the aryl, heteroaryl, cycloalkyl and heterocyclic group is optionally fused to the lactam ring structure.
Specifically, in reaction lactam 26 is formed from an appropriate unsaturated amide 24) through a ruthenium or molybdenum complexes catalyzed olefin metathesis reaction to form unsaturated lactam 25 which can be used herein without further modification. However, the unsaturation in permits a myriad of techniques such as hydroboration, Sharpless or Jacobsen epoxidations, Sharpless dihydroxylations, Diels-Alder additions, dipolar cycloaddition reactions and many more chemistries to provide for a wide range WO 98/28268 PCT/US97/22986 177 of substituents on the lactam ring. Moreover, subsequent transformations of the formed substitution leads to other additional substituents mesylation of an alcohol followed by nucleophilic substitution reactions). See, for example, March, et al. for a recitation of numerous such possible reactions.
28 Saturated amides used in this reaction are conventional with amide 24 being commercially available.
Related chemistry to cyclize amides to form lactams is disclosed by Colombo, et al., Tetrahedron Lett., 35(23):4031-4034 (1994) 29 and is illustrated in reaction (11) below: AcHN N AcHN N (Reaction 11) 00
CO
2 tBu C0 2 tBu 22 2A In this reaction, proline derivative 27 is cyclized via a tributyltin-radical cyclization to provide for lactam 28.
Some of the lactams described above contain the requisite amino group alpha to the lactam carbonyl whereas others did not. However, the introduction of the required amino group can be achieved by any of several routes delineated below which merely catalogue several recent literature references for this synthesis.
For example, in a first general synthetic procedure, azide or amine displacement of a leaving group alpha to the carbonyl group of the lactam leads WO 98/28268 PCT/US97/22986 178 to the alpha-aminolactams. Such general synthetic procedures are exemplified by the introduction of a halogen atom followed by displacement with phthalimide anion or azide and subsequent conversion to the amine typically by hydrogenation for the azide as described in Rogriguez, et al., Tetrahedron, 52:7727-7736 (1996)30, Parsons, et al., Biochem. Biophys. Res. Comm., 117:108-113 (1983) 31 and Watthey, et al., J. Med. Chem., 28:1511-1516 (1985) 32 One particular method involves iodination and azide displacement on, for example, benzyllactams as described by Armstrong, et al., Tetrahedron Lett., 35:3239 (1994)" and by King, et al., J. Org. Chem., 58:3384 (1993) 34 Another example of this first general procedure for the synthesis of alpha-aminolactams from the corresponding lactam involves displacement of a triflate group by an azido group as described by Hu, et al., Tetrahedron Lett., 36(21):3659-3662 (1995) 35 Still another example of this first general procedure uses a Mitsunobu reaction of an alcohol and a nitrogen equivalent (either -NH 2 or a phthalimido group) in the presence of an azodicarboxylate and a triarylphosphine as described in Wada, et al., Bull. Chem. Soc. Japan, 46:2833-2835 (1973) 36 using an open chain reagent.
Yet another example of this first general procedure involves reaction of alpha-chlorolactams with anilines or alkyl amines in a neat mixture at 120 0 C to provide for 2-(N-aryl or N-alkyl)lactams as described by Gaetzi, Chem. Abs., 66:28690m.
3 In a second general synthetic procedure, reaction of an enolate with an alkyl nitrite ester to prepare the alpha oxime followed by reduction yields the alpha-aminolactam compound. This general synthetic procedure is exemplified by Wheeler, et al., Organic Syntheses, Coll. Vol. VI, p. 84038 which describes the reaction of isoamyl nitrite with a ketone to prepare the desired oxime. The WO 98/28268 PCT/US97/22986 179 reduction of the oxime methyl ester (prepared from the oxime by reaction with methyl iodide) is described in the J. Med. Chem., 28(12):1886 (1985) 39 and the reduction of alpha-oximino caprolactams by Raney-nickel and palladium catalysts is described by Brenner, et al., U.S. Patent No. 2,938,029.
4 0 In a third general synthetic procedure, direct reaction of an enolate with an electrophilic nitrogen transfer agent can be used. The original reaction employed toluenesulfonyl azide but was improved as described by Evans, et al., J. Am. Chem. Soc., 112:4011-4030 (1990)'. Specifically, direct introduction of an azido group which can be reduced to the amine by hydrogenation is described by Micouin, et al., Tetrahedron, 52:7719-7726 (1996) 42 Likewise, the use of triisopropylbenzenesulfonyl azide as the azide transferring agent for reaction with an enolate is described by Evans, et al., supra. The use of triphenylphosphine to reduce the alpha-azidolactams to the corresponding aminolactams in the benzodiazepine series is disclosed by Butcher, et al., Tetrahedron Lett., 37(37):6685-6688 (1996).
43 Lastly, diazo transfer of betadiketones and subsequent reduction of the diazo group to the amino group is exemplified by Hu, et al., Tetrahedron Lett., 36(21):3659-3662 (1995) 3 5 who used Raney-nickel and hydrogen in acetic acid and acetic anhydride as the solvent.
In a fourth general procedure, N-substituted lactams are first converted to the 3-alkoxycarbonyl derivatives by reaction with a dialkyl carbonate and a base such as sodium hydride. See, for example, M.L. Reupple, et al., J. Am.
Chem. Soc., 93:7021 et seq. (1971) 44 The resulting esters serve as starting materials for conversion to the 3-amino derivatives. This conversion is achieved via the Curtius reaction as shown in reaction (12) below: WO 98/28268 PCT/US97/22986 180 .Ri. R" L-N L-N
L-N
-o r I 0 (Reaction 12) O ROC 0 PHN 0 where Pr is as defined above and R 12 is typically hydrogen, an alkyl or an aryl group.
The Curtius reaction is described by P.A.S. Smith, Organic Reactions, 3:337-449 (1946).
4 5 Depending on the reaction conditions chosen, Pr H or a protecting group such as Boc. For example, when R H, treatment of the acid with diphenylphosphoryl azide in the presence of t-butanol provides the product wherein Pr Boc.
The alpha-aminolactams employed as the cyclic amino compounds 2 in reaction above include ring N-substituted lactams in addition to ring N-H lactams. Some methods for preparing ring N-substituted lactams have been described above. More generally, however, the preparation of these compounds range from the direct introduction of the substituent after lactam formation to essentially introduction before lactam formation. The former methods typically employ a base and an primary alkyl halide although it is contemplated that a secondary alkyl halide can also be employed although yields may suffer.
Accordingly, a first general method for preparing N-substituted lactams is achieved via reaction of the lactam with base and alkyl halide (or acrylates in some cases). This reaction is quite well known and bases such as sodamide, sodium hydride, LDA, LiHMDS in appropriate solvents such as THF, DMF, etc. are employed provided that the selected base is compatible with the WO 98/28268 PCT/US97/22986 181 solvent. See for example: K. Orito, et al., Tetrahedron, 36:1017-1021 (1980) 4 and J.E. Semple, et al., J. Med. Chem., 39:4531-4536 (1996) 1 9 (use of LiHMDS with either R-X or acrylates as electrophiles).
A second general method employs reductive amination on an amino function which is then cyclized to an appropriate ester or other carbonyl function.
A third general method achieves production of the N-substitution during lactam formation. Literature citations report such production from either photolytic or thermal rearrangement of oxaziridines, particularly of N-aryl compounds. See, for example, Krimm, Chem. Ber., 91:1057 (1958) 4 7 and Suda, et al., J. Chem. Soc. Chem Comm., 949-950, (1994).
48 Also, the use of methyl hydroxylamine for the formation of nitrones and their rearrangement to the N-methyl derivatives is reported by Barton, et al., J. Chem. Soc., 1764- 1767 (1975).
49 Additionally, the use of the oxaziridine process in chiral synthesis has been reported by Kitagawa, et al., J. Am. Chem. Soc., 117:5169- 5178 (1975).
5 0 A more direct route to obtain N-phenyl substituted lactams from the corresponding NH lactams through the use of t-butyltetramethylguanidine and triphenylbismuth dichloride is disclosed by Akhatar, et al., J. Org. Chem., 55:5222-5225 (1990)" 5 as shown in reaction (13) below.
0 0 n (Reaction 13) WO 98/28268 WO 98/28268 PCT/US97/22986 182 Given that numerous methods are available to introduce an alpha-amino group onto a lactam (or lactone) ring, the following lactams (and appropriate corresponding lactones) are contemplated for use in the synthesis of compounds of formula I above. Similar alcohol functions at the carbonyl position are derivative of either amine ring opening of cyclic epoxides, ring opening of aziridines, displacement of appropriate halides with amine or alcohol nucleophiles, or most likely reduction of appropriate ketones. These ketones are also of interest to the present invention.
Monocyclic lactams as described by Nedenskov, et al., Acta Chem.
Scand., 12:1405-1410 (1958) 52 are represented by the formula: 0
NH
NH R 1
R
2 where R, and R 2 are exemplified by alkyl, aryl or alkenyl allyl).
Monocyclic lactams containing a second nitrogen ring atom as described by Sakakida, et al., Bull. Chem. Soc. Japan, 44:478-480 (1971) 53 are represented by the formula:
O
NH
R
where R is exemplified by CH 3 or PhCH,-.
WO 98/28268 PCT/US97/22986 183 Monocyclic lactams having hydroxyl substitution on the ring as described by Hu, et al., Tetrahedron Lett., 36(21):3659-3662 (1995) 3 5 are represented by the formula:
NR
R
where R is exemplified by benzyl (includes both the cis and trans hydroxy lactams).
The direct preparation N-substituted lactams of 5-8 members from the corresponding ketones is described by Hoffman, et al., Tet. Lett., 30:4207-4210 (1989).
54 These lactams are represented by the formula: 0
(CH
2 )n n=1 -4
-(CH
2 )n wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, or benzyl.
N-Methoxylactams prepared from cyclohexanone and dimethoxyamine are described by Vedejs, et al., Tet. Lett., 33:3261-3264 (1992).
5 5 These structures are represented by the formula: WO 98/28268 PCTIUS97/22986 184-- 01
CH
3 Substituted 3-aminoazetidinone derivatives prepared by a variety of routes including those described by van der Steen, et al., Tetrahedron, 47, 7503-7524 (1991) 5 6 Hart, et al., Chem Rev., 89:1447-1465 (1989) 5 7 and references cited therein are represented by the formula:
H
2
N
0 RO where R, and R 2 are independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, heterocyclic or are fused to form a cyclic group.
Ring substituted lactams are described by Lowe, et al., Bioorg. Med.
Chem. Lett., 4:2877-2882 (1994) 58 and are represented by the formula:
H
2
N
WO 98/28268 PCT/US97/22986 185 wherein R 2 and R 3 are exemplified by aryl and substituted aryl and R, is exemplified by alkyl or hydrogen.
The synthesis of substituted 3-aminopyrrolidones from alphabromoketones is described by McKennis, Jr., et al., J. Org. Chem., 28:383-387 (1963) 59 These compounds are represented by the formula: 0 Rj Br
NH
2 R4 2 where R' is aryl or heteroaryl and R 2 corresponds to any substituent for which the corresponding amine R 2
-NH
2 exists.
Additional references for the synthesis of alpha aminolactams are as follows: 1. Shirota, et al., J. Med. Chem., 20:1623-1627 (1977) 0 which describes the synthesis of
CH
3
CH
3
H
2
N
2. Overberger, et al., J. Am. Chem. Soc., 85:3431 (1963) 6 1 which describes the preparation of optically active i-methylcaprolactam of the formula: WO 98/28268 OCT/US97/22986 186-- 3. Herschmann, Helv. Chim. Acta, 32:2537 (1949)62 describes the synthesis of a disubstituted caprolactam. from the Beckman rearrangement of menthone which is represented by the formula: 1
N
4. Overberger, et al., Macromolecules, 1:1 (1968)63 describes the synthesis of eight-membered lactams from 3-methylcycloheptanone as shown below:
N
The synthesis of benzolactams (benzazepinones) has been reported by Busacca, et al., Tet. Lett_, 33:165-168 (1992)64: WO 98/28268 PCTIUS97/22986 187by Croisier, et al., U.S. Patent No. 4,080,44965: and by J.A. Robi, et al., Tetrahedron Lett., 36(10):1593-1596 (1995)1 who employed an internal Friedel-Crafts like cyclization to prepare the tricyclic benzyl-lactams shown below where Pht is the phthalimido protecting group: Pht=N -N 0 C0 2 Et Pht=N Another tricyclic lactamn series is disclosed by Flynn, et al., Med.
Chem., 36:2420-2423 (1993)67 and references cited therein.
WO 98/28268 PCT/US97/22986 188 6. Orito, et al., Tetrahedron, 36:1017-1021 (1980) 6 8 discloses phenyl substituted benzazepinones represented by the formula: wherein R H or CH 3 Kawase, et al., J. Org. Chem., 54:3394-3403 (1989) 69 discloses a Nmethoxy benzazepinone represented by the formula: 0,
CH
3 7. Lowe, et al., J. Med. Chem., 37:3789-3811 (1994) 7 0 describes several synthetic pathways to substituted benzazepinones of the formula: R
N
Ei /NH where R, is substituted aryl or cyclohexyl, X is a suitable substituent and R, can be H or alkyl. The syntheses described in Lowe are, however, adaptable to form numerous R' substituents.
WO 98/28268 PCT/US97/22986 189 8. Robl, et al., Bioorg. Med. Chem. Lett., 4:1789-1794 (1994) 71 and references cited therein as well as Skiles, et al., Bioorg. Med. Chem. Lett., 3:773-778 (1993) 7 2 disclose benzofused lactams which contain additional heteroatoms in the lactam ring. These compounds are represented by the formula: R2 X
NH
2 N NH
R
R,
where X is O and R 2 H or CH3 or X S and R 2 H. In either case, R H or alkyl. Also, in Skiles, the thio group of the thiolactam can be oxidized to the SO 2 group. These structures are also presented from Beckmann rearrangement in Grunewald, et al., J. Med. Chem., 39(18):3539 (1996).
73 9. Also syntheses for the benzoheterolactam series is presented in Thomas, et al., J. Chem. Soc., Perkin II, 747 (1986) 7 4 which could lead to compounds of the formula:
NH
2
X
0 N-N
R-'
X O, H 2 R CO 2
R
where X is O or H, and R is CO 2
R.
WO 98/28268 PCTIUS97/22986 190-- Further examples of benzazepinones are found in Warshawsky, et al., Bioorg. Med. Chem. Lett., 6:957-962 (1996)"~ which discloses
H
2
N
The synthesis can be generalized to produce R alkyl or aryl.
11.- Ben-Ishai, et al., Tetrahedron, 43:439-450 (1987)76 describes syntheses which could lead to several benzolactamns of the formula
H
2 N 0 wherein n 0, 1,2 and R -CH 3 PhCH,- and H.
12. van Niel et al., Bioorg. Med. Chrem. Len.. 5:1421-1426 (1995)77 reports the synthesis of WO 98/28268 PCTUS9722986 191
H
3
C
H
3
C
NH
2 *NHBoc wherein X is -OH, -NH 2 or -NRR 6 where R 6 is as defined above. The reported ketone is a versatile synthetic intermediate which can be modified by conventional methods such as reductive amination, reduction, etc.
13. Kawase, et al., J. Org. Chem., 54:3394-3403 (1989) 7 8 describes a synthetic method for the preparation of:
OCH
3 In addition to the above, saturated bicyclic alpha-aminolactams are also contemplated for use in the synthesis of compounds of formula I. Such saturated bicyclic alpha-aminolactams are well known in the art. For example, Edwards, et al., Can. J. Chem., 49:1648-1658 (1971) 7 9 describes several syntheses of bicyclic lactams of the formula: 0 o 0
N
0 WO 98/28268 PCT/US97/22986 192 Similarly, Milligan, et al., J. Am. Chem. Soc., 117:10449-10459 (1995) 8 0 and references cited therein report the synthesis of lactams of the formula: 0 R2 0 N6
N
N A B
RR
wherein R1 and R2 are H or -CH 3 ring A can have from 6-13 members and ring B can have from 5 7 members. R can be alkyl, aryl, cycloalkyl, and the like.
The introduction of a heteroatom into the saturated cyclic structure fused to the lactam ring is disclosed by Curran et al., Tet. Lett., 36:191-194 (1995)81 who describe a synthetic method which can be used to obtain a lactam of the formula: 020 N N O
NH
2 by Slusarchyk, et al., Bioorg. Med. Chem. Lett., 5:753-758 (1995)82 who describe syntheses which could lead to a lactam of the formula: WO 98/28268 PCT1US97t22986 -193 and by Wyvratt, et al., Eur. Pat. AppI. 61187 (1982)813 who describe a lactamn of the formula:
S
H
2
N
0 Lactams having further heteroatom(s) in the cyclic lactamn structure (in addition to the nitrogen of the amido group of the lactaxn) are described by Cornille, et al., J. Am. Chem. Soc., 17.:909-917 (1995)"' who describe lactams of the formula.: H 2
N,
0 J. Koic. Coil. Czech. Chem. Comm_, 34:630 (1969)1 who describes lysines suitable for cyclization to lactams which have a hetero lactarn ring atom as shown by the formula: -u
H
2 N 7X 00 H NH 2
H
where X=O, S and NR where R is, for example, alkyl, substituted alkyl, aryl.
heteroaryl, heterocyclic, and the like.
WO 98/28268 PCT/US97/22986 194 Similarly, each of Dickerman, et al., J. Org. Chem., 14:530 (1949)8 6 Dickerman, et al., J. Org. Chem., 20:206 (1955)87, and Dickerman, et al., J.
Org. Chem., 19:1855 (1954) 88 used the Schmidt and Beckmann reactions on substituted 4-piperidones to provide for lactams of the formula: R ,R R'
-R
HN
H
where R is acyl, alkyl, substituted alkyl, aryl, heteroaryl or heterocyclic provided that R is not an acid labile group such as t-Boc; and R' is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclicoxy, halo, cyano, nitro, trihalomethyl, and the like.
An internal cyclization of appropriate ethylenediamine amides onto a ketone or aldehyde is described by Hoffman, et al., J. Org. Chem., 27:3565 (1962)89 as follows:
R
z R H O N
N
H I R Methyl, Phenyl Ring expansion methodology based on beta lactams to provide for larger ring lactams containing an aza group has twice been reported in Wasserman, et al., J. Am. Chem. Soc., 103:461-2 (1981) 9 and in Crombie, et al., Tetrahedron Lett., 27(42):5151-5154 (1986).
91 WO 98/28268 PCT/US97/22986 195 Dieckmann methodology has been used to prepare aza caprolactams from unsymmetrical amines such as shown below by Yokoo, et al., Bull, Chem.
Soc. Jap., 29:631 (1956).
9
R
CO
2 Et
CO
2 Et N
H
where R is as defined in this reference. The disclosure of Yokoo, et al. can be extended to cover R being alkyl, substituted alkyl, aryl, alkoxy, substituted alkoxy, heteroaryl, cycloalkyl, heterocyclic, alkenyl, substituted alkenyl, and the like.
The synthesis of various members of the oxalactam series has been reported by Burkholder, et al., Bioorg. Med. Chem. Lett., 2:231 (1993) 93 and references cited therein which oxalactams are represented by the formula: 'RHN 0 0
N
R
where 'R is as defined in the reference and R can be alkyl, substituted alkyl, aryl, alkoxy, substituted alkoxy, heteroaryl, cycloalkyl, heterocyclic, alkenyl, substituted alkenyl, and the like.
WO 98/28268 PCT/US97/22986 196 The synthesis of thialactams (generally oxalactams can be made by the same methodology) has been reported by Freidinger, et al., J. Org. Chem., 47:104-109 (1982)18 who prepared thialactams of the formula:
H
2
N
This reference provides a series of procedures having broad application for synthesis of lactams permitting R in the above formula to be derived from any amine (alkyl, aryl, heteroaryl, etc.) with the restriction being that the R-group does not contain any functional groups reactive with formaldehyde primary and secondary amines). The general synthetic scheme provided by Freidlinger, et al. is: H
H
f-N pN 0 S 0 S 0 coupling O S+ R-NH 2 agent OH NHR 0 0 0 0 paraformaidehyde O N-methylhydrazine S p-TosOH N R H 2
CI
2 CHCHCI 0 -0 The coupling agent is any standard reagent used in the formation of typical peptide or amide bonds, for example, carbodiimide reagents. See, also.
WO 98/28268 PCTI[S97I22986 197-- Karanewsky, U.S. Patent No. 4,460,57994 and Kametani, et al., Heterocycles, 9:831-840 (1978).9' The Friedinger procedure can be extended to afford disubstituted thialactams of the following structure: .S
R
2
H
2 N N-R 0 to 150 0 rR 2
NR,
coupling agent 0 S y-rR2 N5 N,.
0 0 In practical terms, R 2 will be limited to aryl and heteroaryl groups and sterically hindered alkyl groups such as t-butyl. R, can be highly variable and is limited only by subsequent reaction steps.
Still further is the Kametani procedure which provides for lactams, as follows: 0 cc NHR 0 0 0 P-TosOH 0 Y~R benzene N NR 0 0 WO 98/28268 PCT/US97/22986 198 In principle, the Kametani procedure allows for a wide selection of RI and R2 groups limited primarily by stability to the reaction conditions.
See, for example, Yanganasawa, et al., J. Med. Chem., 30:1984-1991 (1987) 9 and J..Das et al., Biorg. Med. Chem. Lett., 4:2193-2198 (1994) 97 which describes general methods for the synthesis of isomeric 7-membered thialactams of the following structure: The first synthetic route is:
SH
-BocHN OH 0 O 1. Cyclization 2. Selective alkyl;ation R2
NO
2 1. N-methylmorpholine 2. Reduction BocHN
NH
2
R
2
N
R,
R
2 can be highly variable alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic and the like) since a number of well documented routes exist for the synthesis of nitroethylene derivatives from aldehydes and nitromethane (Henry reaction) followed by dehydration. R, is limited to groups that can undergo alkylation reactions.
WO 98/28268 PCT/US97/22986 199 The second compound series can be prepared as follows: NHBoc 0 O
R
2 NHBoc N S R 2 .0 N- N- OCHPh 2 OMs OCHPh 2 00 00
S
1. Protecting group removal R2
H
2
N
2. Cyclization R, 3. Selective alkylation (R 1 4. Methylhydrazine In this synthesis, R 2 can be highly variable. The starting component required to introduce R 2 can be readily derived by the reduction of any known alpha-BOCamino acid to the alcohol derivative followed by formation of the mesylate.
As noted above, the primary approaches to the preparation of lactams is the Beckmann/Schmidt ring expansion reaction using either inter- or intramolecular approaches serves to prepare lactams of various ring sizes. The intramolecular approach generates bicyclic materials with the lactam nitrogen incorporated into the ring fusion. Additional approaches set forth above are at the base of the methodology are internal cyclization of omega-amino acids/esters where the construction of the substituent pattern takes place prior to cyclization, and internal cyclization of an electrophilic center onto a nucleophilic functional group as in the Friedel Crafts type cyclization at the center of the Ben-Ishal procedure for making benzazepinones. This latter procedure is applicable to a wide variety of heteroaromatics as well as benzenoid rings, and may also be applied to non-aromatic double or triple bonds to generate a wide array of substituents or ring fusions.
WO 98/28268 PCT/US97/22986 200 Deoxygenation of the lactam by reagents such as diborane, LiAlH 4 and the like leads to azaheterocycles is dihydro).
Similarly, for X H, OH, such compounds can be prepared by epoxidation of cycloalkenyl groups followed by oxirane opening by, e.g., ammonia. After formation of compounds of formula I, =X being H, OH can be oxidized to provide for cycloalkylones being oxo).
Additionally, the 5,7-dihydro-6H-diben[b,d]azepin-6-one derivatives employed in this invention can be prepared using conventional procedures and reagents. For example, an appropriately substituted N-tert-Boc-2-amino-2'methylbiphenyl compound can be cyclized to form the corresponding 5,7dihydro-6H-diben[b,d]azepin-6-one derivative by first treating the biphenyl compound with about 2.1 to about 2.5 equivalents of a strong base, such as secbutyl lithium. This reaction is typically conducted at a temperature ranging from about -80*C to about -60°C in an inert diluent such as THF. The resulting dianion is then treated with dry carbon dioxide at a temperature of about -78*C to afford the 5,7-dihydro-6H-diben[b,d]azepin-6-one. This procedure is described further in R. D. Clark et al., Tetrahedron, 49(7), 1351- 1356 (1993) and references cited therein.
After forming the 5,7-dihydro-6H-diben[b,d]azepin-6-one, the amide nitrogen can be readily alkylated by first treating the dibenazepinone with about 1.1 to about 1.5 equivalents of a strong base, such as sodium hydride, in an inert diluent, such as DMF. This reaction is typically conducted at a temperature ranging from about -10°C to about 80 0 C for about 0.5 to about 6 hours. The resulting anion is then contacted with an excess, preferably about 1.1 to about 3.0 equivalents, of an alkyl halide, typically an alkyl chloride, bromide or iodide. Generally, this reaction is conducted at a temperature of about 0°C to about 100 0 C for about 1 to about 48 hours.
WO 98/28268 PCT/US97122986 201 An amino group can then be introduced at the 5-position of the 7-alkyl- 5,7-dihydro-6H-diben[b,d]azepin-6-one using conventional procedures and reagents. For example, treatment of 7-methyl-5,7-dihydro-6Hdiben[b,d]azepin-6-one with an excess of butyl nitrite in the presence of a strong base, such as potassium 1,1,1,3,3,3-hexamethyldisilazane (KHMDS), affords 5-oximo-7-methyl-5,7-dihydro-6H-diben[b,d]azepin-6-one. Subsequent reduction of the oximo group by hydrogenation in the presence of a catalyst, such as palladium on carbon, then provides 5-amino-7-methyl-5,7-dihydro-6Hdiben[b,d]azepin-6-one. Other conventional amination procedures, such as azide transfer followed by reduction of the azido group, may also be employed.
Similarly, various benzodiazepine derivatives suitable for use in this invention can be prepared using conventional procedures and reagents. For example, a 2-aminobenzophenone can be readily coupled to a-(isopropylthio)- N-(benzyloxycarbonyl)glycine by first forming the acid chloride of the glycine derivative with oxayl chloride, and then coupling the acid chloride with the 2aminobenzophenone in the presence of a base, such as 4-methylmorpholine, to afford the 2-[a-(isopropylthio)-N-(benzyloxycarbonyl)glycinyl]aminobenzophenone. Treatment of this compound with ammonia gas in the presence of an excess, preferably about 1.1 to about 1.5 equivalents, of mercury (II) chloride then affords the 2-[N-(ao-amino)-N'-(benzyloxycarbonyl)glycinyl]aminobenzophenone. This intermediate can then be readily cyclized by treatment with glacial acetic acid and ammonium acetate to provide the 3- (benzyloxycarbonyl)amino-2,3-dihydro-5-phenyl-lH-1,4-benzodiazepin-2-onel.
Subsequent removal of the Cbz group affords the 3-amino-2,3-dihydro-5phenyl- 1H-1,4-benzodiazepin-2-one.
Alternatively, 2,3-dihydro-5-phenyl-lH-1,4-benzodiazepin-2-ones can be readily aminated at the 3-position using conventional azide transfer reactions followed by reduction of the resulting azido group to form the corresponding amino group. The conditions for these and related reactions are described in WO 98/28268 PCT/US97/22986 202 the examples set forth below. Additionally, 2,3-dihydro-5-phenyl-1H-l,4benzodiazepin-2-ones are readily alkylated at the 1-position using conventional procedures and reagents. For example, this reaction is typically conducted by first treating the benzodiazepinone with about 1.1 to about 1.5 equivalents of a base, such as sodium hydride, potassium tert-butoxide, potassium 1,1,1,3,3,3hexamethyldisilazane, cesium carbonate, in an inert diluent, such as DMF.
This reaction is typically conducted at a temperature ranging from about -78°C to about 80*C for about 0.5 to about 6 hours. The resulting anion is then contacted with an excess, preferably about 1.1 to about 3.0 equivalents, of an alkyl halide, typically an alkyl chloride, bromide or iodide. Generally, this reaction is conducted at a temperature of about 0°C to about 100°C for about 1 to about 48 hours.
Additionally, the 3-amino-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5benzodiazepines employed in this invention are typically prepared by first coupling malonic acid with a 1,2-phenylenediamine. Conditions for this reaction are well known in the art and are described, for example, in PCT Application WO 96-US8400 960603. Subsequent alkylation and amination using conventional procedures and reagents affords various 3-amino-1,5bis(alkyl)-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepines. Such procedures are described in further detail in the example set forth below.
Accordingly, a vast number of lactams, lactones and thiolactones are available by art recognized procedures. Similarly, the art is replete with examples of aminocycloalkyl compounds for use in the synthesis of compounds of formula I above.
In the synthesis of compounds of formula I using the synthetic methods described above, the starting materials can contain a chiral center alanine) and, when a racemic starting material is employed, the resulting product is a mixture of R,S enantiomers. Alternatively, a chiral isomer of the starting WO 98/28268 PCT/US97/22986 203 material can be employed and, if the reaction protocol employed does not racemize this starting material, a chiral product is obtained. Such reaction protocols can involve inversion of the chiral center during synthesis.
Accordingly, unless otherwise indicated, the products of this invention are a mixture of R,S enantiomers. Preferably, however, when a chiral product is desired, the chiral product corresponds to the L-amino acid derivative.
Alternatively, chiral products can be obtained via purification techniques which separates enantiomers from a R,S mixture to provide for one or the other stereoisomer. Such techniques are well known in the art.
Pharmaceutical Formulations When employed as pharmaceuticals, the compounds of formula I are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of formula I above associated with pharmaceutically acceptable carriers. In making the compositions of this invention, the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by WO 98/28268 PCT/US97/22986 204 weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Preferably, the compound of formula I above is employed at no more than about 20 weight percent of the WO 98/28268 PCT/US97/22986 205 pharmaceutical composition, more preferably no more than about 15 weight percent, with the balance being pharmaceutically inert carrier(s).
The active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It, will be understood, however, that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can separated by enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number WO 98/28268 PCT/US97/22986 206 of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
The following formulation examples illustrate the pharmaceutical compositions of the present invention.
Formulation Example 1 Hard gelatin capsules containing the following ingredients are prepared: Quantity Ingredient (mg/caDsule) Active Ingredient 30.0 Starch 305.0 Magnesium stearate WO 98/28268 PCT/US97/22986 207 The above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
Formulation Example 2 A tablet formula is prepared using the ingredients below: Quantity Ingredient (mg/tablet) Active Ingredient 25.0 Cellulose, microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid The components are blended and compressed to form tablets, each weighing 240 mg.
Formulation Example 3 A dry powder inhaler formulation is prepared containing the following components: Ingredient Weight Active Ingredient Lactose The active ingredient is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
WO 98/28268 PCT/US97/22986 208 Formulation Example 4 Tablets, each containing 30 mg of active ingredient, are prepared as follows: Quantity Ingredient (me/tablet) Active Ingredient 30.0 mg Starch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone (as 10% solution in sterile water) 4.0 mg Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1.0 mg Total 120 mg The active ingredient, starch and cellulose are passed through a No. mesh U.S. sieve and mixed thoroughly. The solution of polyvinyl-pyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50* to 60*C and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
Formulation Example Capsules, each containing 40 mg of medicament are made as follows: Quantity Ingredient (mg/capsule) Active Ingredient 40.0 mg Starch 109.0 mg Magnesium stearate 1.0 me Total 150.0 mg WO 98/28268 PCTIUS97/22986 209 The active ingredient, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
Formulation Example 6 Suppositories, each containing 25 mg of active ingredient are made as follows: Ingredient Amount Active Ingredient 25 mg Saturated fatty acid glycerides to 2,000 mg The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.
Formulation Example 7 Suspensions, each containing 50 mg of medicament per 5.0 ml dose are made as follows: Ingredient Amount Active Ingredient 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethyl cellulose (11%) Microcrystalline cellulose 50.0 mg Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v.
Purified water to 5.0 ml The active ingredient, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in WO 98/28268 PCTUS97/22986 210 water. The sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
Formulation Example 8 Quantity Ingredient (mg/capsule) Active Ingredient 15.0 mg Starch 407.0 mg Magnesium stearate 3.0 mg Total 425.0 mg The active ingredient, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 560 mg quantities.
Formulation Example 9 A subcutaneous formulation may be prepared as follows: Ingredient Ouantity Active Ingredient 1.0 mg corn oil 1 ml (Depending on the solubility of the active ingredient in corn oil, up to about 5.0 mg or more of the active ingredient may be employed in this formulation, if desired).
Formulation Example A topical formulation may be prepared as follows: Ingredient Quantity Active Ingredient 1-10 g Emulsifying Wax 30 g Liquid Paraffin 20 g White Soft Paraffin to 100 g WO 98/28268 PCTIUS97/22986 211 The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirring is continued until dispersed. The mixture is then cooled until solid.
Another preferred formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, U.S. Patent 5,023,252, issued June 11, 1991, herein incorporated by reference. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
Frequently, it will be desirable or necessary to introduce the pharmaceutical composition to the brain, either directly or indirectly. Direct techniques usually involve placement of a drug delivery catheter into the host's ventricular system to bypass the blood-brain barrier. One such implantable delivery system used for the transport of biological factors to specific anatomical regions of the body is described in U.S. Patent 5,011,472 which is herein incorporated by reference.
Indirect techniques, which are generally preferred, usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs. Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier. Alternatively, the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.
WO 98/28268 PCTIUS97/22986 212 Other suitable formulations for use in the present invention can be found in Remington's Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, PA, 17th ed. (1985).
Utility The compounds and pharmaceutical compositions of the invention are useful in inhibiting -amyloid peptide release and/or its synthesis, and, accordingly, have utility in diagnosing and treating Alzheimer's disease in mammals including humans.
As noted above, the compounds described herein are suitable for use in a variety of drug delivery systems described above. Additionally, in order to enhance the in vivo serum half-life of the administered compound, the compounds may be encapsulated, introduced into the lumen of liposomes, prepared as a colloid, or other conventional techniques may be employed which provide an extended serum half-life of the compounds. A variety of methods are available for preparing liposomes, as described in, Szoka, et al., U.S.
Patent Nos. 4,235,871, 4,501,728 and 4,837,028 each of which is incorporated herein by reference.
The amount of compound administered to the patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions are administered to a patient already suffering from AD in an amount sufficient to at least partially arrest further onset of the symptoms of the disease and its complications. An amount adequate to accomplish this is defined as "therapeutically effective dose." Amounts effective for this use will depend on the judgment of the attending clinician depending upon factors such as the degree or severity of AD in the patient, the age, weight and general condition of the patient, and the like.
WO 98/28268 PCT/US9/298 213 Preferably, for use as therapeutics, the compounds described herein are administered at dosages ranging from about 1 to about 500 mg/kg/day.
In prophylactic applications, compositions are administered to a patient at risk of developing AD (determined for example by genetic screening or familial trait) in an amount sufficient to inhibit the onset of symptoms of the disease.
An amount adequate to accomplish this is defined as "prophylactically effective dose." Amounts effective for this use will depend on the judgment of the attending clinician depending upon factors such as the age, weight and general condition of the patient, and the like. Preferably, for use as prophylactics, the compounds described herein are administered at dosages ranging from about 1 to about 500 mg/kg/day.
As noted above, the compounds administered to a patient are in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered.
The resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 and 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
The compounds described herein are also suitable for use in the administration of the compounds to a cell for diagnostic and drug discovery purposes. Specifically, the compounds may be used in the diagnosis of cells releasing and/or synthesizing 0-amyloid peptide. In addition the compounds described herein are useful for the measurement and evaluation of the activity of other candidate drugs on the inhibition of the cellular release and/or synthesis of 0-amyloid peptide.
WO 98=2268 PCT/US97/22986 214 The following synthetic and biological examples are offered to illustrate this invention and are not to be construed, in any way as limiting the scope of this invention.
EXAMPLES
In the examples below, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.
BEMP
Boc
BOP
bd bs d dd
DIC
DMF
DMAP
DMSO
EDC
eq.
EtOAc g
HOBT
Hunig's base
L
m
M
max meq mg
ML
mm nunol
MOC
N
N/A
ng rim
OD
PEPC
2-tert-butylimino-2-diethylamino- 1,3dimethylperhydro- 1,3 ,2-diazaphosphorine t-butoxycarbonyl benzotriazol- 1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate broad doublet broad singlet doublet doublet of doublets diisopropylcarbodiimide dimethylformamide dimethylaminopyridine dimethylsulfoxide ethyl- 1-(3-dimethyaminopropyl)carbodiimide equivalents ethyl acetate grams 1-hydroxybenzotriazole hydrate diisopropylethylamine liter multiplet molar maximum milliequivalent milligram milliliter millimeter millimole methoxyoxycarbonyl normal not available nanogram nanometers optical density 1 -(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide WO 98/28268 PCT/US97/22986 215 PP-HOBT piperidine-piperidine- 1-hydroxybenzotrizole psi pounds per square inch 04 phenyl q quartet quint. quintet rpm rotations per minute s singlet t triplet TFA trifluoroacetic acid THF tetrahydrofuran tic thin layer chromatography 1L microliter UV ultra-violet In the examples below, all temperatures are in degrees Celcius (unless otherwise indicated). The compounds set forth in the examples below were prepared using the following general procedures as indicated.
In the following examples and procedures, the term "Aldrich" indicates that the compound or reagent used in the procedure is commercially available from Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, WI 53233 USA; the term "Fluka" indicates that the compound or reagent is commercially available from Fluka Chemical Corp., 980 South 2nd Street, Ronkonkoma NY 11779 USA; the term "Lancaster" indicates that the compound or reagent is commercially available from Lancaster Synthesis, Inc., P.O. Box 100 Windham, NH 03087 USA; the term "Sigma" indicates that the compound or reagent is commercially available from Sigma, P.O. Box 14508, St. Louis MO 63178 USA; the term "Chemservice" indicates that the compound or reagent is commercially available from Chemservice Inc., Westchester, PA; the term "Bachem" indicates that the compound or reagent is commercially available from Bachem Biosciences Inc., 3700 Horizon Drive, Renaissance at Gulph Mills, King of Prussia, PA 19406 USA; the term "Maybridge" indicates that the compound or reagent is commercially available from Maybridge Chemical Co. Trevillett, Tintagel, Cornwall PL34 OHW United Kingdom; and the term "TCI" indicates that the compound or reagent is commercially available from TCI America, 9211 North Harborgate Street, WO 98/28268 PCT/US97/22986 216 Portland OR 97203; the term "Alfa" indicates that the compound or reagent is commercially available from Johnson Matthey Catalog Company, Inc. 30 Bond Street, Ward Hill, MA 01835-0747; the term "Novabiochem" indicates that the compound or reagent is commercially available from Calbiochem-Novabiochem Corp. 10933 North Torrey Pines Road, P.O. Box 12087, La Jolla CA 92039- 2087; the term "Oakwood" indicates that the compound or reagent is commercially available from Oakwood, Columbia, South Carolina; the term "Advanced Chemtech" indicates that the compound or reagent is commercially available from Advanced Chemtech, Louisville, KY; and the term "Pfaltz Bauer" indicates that the compound or reagent is commercially available from Pfaltz Bauer, Waterbury, CT, USA.
I. Coupling Procedures GENERAL PROCEDURE A First EDC Coupling Procedure To a 1:1 mixture of the corresponding carboxylic acid and the corresponding amino acid ester or amide in CH 2 C1 2 at O*C was added equivalents triethylamine, followed by 2.0 equivalents hydroxybenzotriazole monohydrate and then 1.25 equivalents of ethyl-3-(3-dimethylamino)propyl carbodiimide-HC1. The reaction mixture was stirred overnight at room temperature and then transferred to a separatory funnel. The mixture was washed with water, saturated aqueous NaHCO 3 IN HCI and saturated aqueous NaC1, and then dried over MgSO 4 The resulting solution was stripped free of solvent on a rotary evaporator to yield the crude product.
GENERAL PROCEDURE B Second EDC Coupling Procedure A mixture of the corresponding acid (1 eqv), N-l-hydroxybenzotriazole (1.6 eqv), the corresponding amine (1 eqv), N-methylmorpholine 3 eqv) and dichloromethane (or DMF for insoluble substrates) was cooled in an ice-water WO 98/28268 PCT/US97122986 217 bath and stirred until a clear solution was obtained. EDC (1.3 eqv) was then added to the reaction mixture. The cooling bath was then allowed to warm to ambient temperature over 1-2 h and the reaction mixture was stirred overnight.
The reaction mixture was then evaporated to dryness under vacuum. To the residue was added 20% aqueous potassium carbonate and the mixture was shaken throughly and then allowed to stand until the oily product solidified (overnight if necessary). The solid product was then collected by filteration, washed thoroughly with 20% aqueous potassium carbonate, water, 10% HC1, and water to give the product, usually in pure state. No racemization was observed.
GENERAL PROCEDURE C Third EDC Coupling Procedure The carboxylic acid was dissolved in methylene chloride. The corresponding amino acid ester or amide (1 N-methylmorpholine (5 eq.) and hydroxybenzotriazole monohydrate (1.2 eq.) were added in sequence. A cooling bath was applied to the round bottomed flask until the solution reached 0 C. At that time, 1.2 eq. of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added. The solution was allowed to stir overnight and come to room temperature under nitrogen pressure. The reaction mixture was worked up by washing the organic phase with saturated aqueous sodium carbonate, 0.1M citric acid, and brine before drying with sodium sulfate. The solvents were then removed to yield crude product.
GENERAL PROCEDURE D Fourth EDC Coupling Procedure A round bottom flask was charged with the corresponding carboxylic acid hydroxybenzotriazole hydrate (1.1 eq.) and the corresponding amine eq.) in THF under nitrogen atmosphere. An appropriate amount (1.1 eq for free amines and 2.2 eq. for hydrochloride amine salts) of base, such as Hunig's base was added to the well stirred mixture followed by EDC (1.1 After WO 98/28268 PCT/US97/22986 218 stirring from 4 to 17 hours at room temperature the solvent was removed at reduced pressure, the residue taken up in ethyl acetate (or similar solvent) and water, washed with saturated aqueous sodium bicarbonate solution, 1 N HCI, brine, dried over anhydrous sodium sulfate and the solvent removed at reduced pressure to provide the product.
GENERAL PROCEDURE E BOP Coupling Procedure To a stirred solution of N-(3,5-difluorophenylacetyl)alanine (2 mmol) in DMF, cooled in an ice-water bath, was added BOP (2.4 mmol) and Nmethylmorpholine (6 mmol). The reaction mixture was stirred for 50 min. and then a solution of ao-amino-y-lactam (2 mmol) in DMF cooled at 0 *C was added. The cooling bath was allowed to warm to ambient temperature over 1-2 h and the reaction mixture was then stirred overnight. A 20% aqueous potassium carbonate solution (60 mL) was added and this mixture shaken throughly. No solid formed. The mixture was then washed with ethyl acetate (150 mL) and evaporated to dryness under vacuum to give a white solid. Water mL) was then added and this mixture shaken throughly. The precipitate that formed was collected by filtration, then washed thoroughly with water, followed by 1 mL of diethyl ether to give the product (51 mg, 0.16 mmol, GENERAL PROCEDURE F Coupling of an Acid Chloride with an Amino Acid Ester To a stirred solution of (D,L)-alanine isobutyl ester hydrochloride (4.6 mmol) in 5 ml of pyridine was added 4.6 mmol of the acid chloride.
Precipitation occurred immediately. The mixture was stirred for 3.5 h, dissolved in 100 mL of diethyl ether, washed with 10% HC1 three times, brine once, potassium carbonate once and brine once. The solution was dried over magnesium sulfate, filtered, and evaporated to yield the product. Other amino acid esters may also be employed in this procedure.
WO 98/28268 PCTfUS97/298 219 GENERAL PROCEDURE G Coupling of a Carboxvlic Acid with an Amino Acid Ester A solution of the carboxylic acid (3.3 mmol) and 1,1'-carbodiimidazole (CDI) in 20 mL THF was stirred for 2 h. (D,L)-alanine isobutyl ester hydrochloride (3.6 mmol) was added, followed by 1.5 mL (10.8 mmol) of triethylamine. The reaction mixture was stirred overnight. The reaction mixture was dissolved in 100 mL of diethyl ether, washed with 10% HCI three times, brine once, 20% potassium carbonate once and brine once. The solution was dried over magnesium sulfate, filtered, and evaporated to yield the product.
Other amino acid esters may also be employed in this procedure.
GENERAL PROCEDURE H Fifth EDC Coupling Procedure In a round bottom flask was added a carboxylic acid (1.1 eq.) in THF, an amine hydrochloride (1.0 1-hydroxybenzotriazole hydrate (1.1 N,Ndiisopropylethylamine (2.1 followed by 1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (EDC) (1.1 The reaction mixture stirred at room temperature for 10-20 hours under an atmosphere of nitrogen. The mixture was diluted with EtOAc and washed with 0.1 M HCI (1 x 10 mL), saturated NaHCO 3 (1 x 10 mL), HO (1 x 10 mL), and brine and dried over MgSO 4 The drying agent was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel followed by trituration from EtOAc and hexanes.
GENERAL PROCEDURE I Sixth EDC Coupling Procedure To a solution or suspension of the amine or amine hydrochloride (1.0 eq.) in THF (0.05-0.1 M) under N 2 at 0°C was added the carboxylic acid (1.0-1.1 hydroxybenzotriazole monohydrate (1.1-1.15 Hunig's base (1.1 eq. for free amines and 1.1-2.3 eq. for hydrochloride amine salts), followed by 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.1-1.15 The WO 98/28268 PCTIUS9722986 220 cooling bath was removed and the mixture allowed to warm to room temperature for 10-24 hours. The solution or mixture was diluted with EtOAc, in a 3-5 volume multiple of the initial THF volume, and washed with 0.1-1.0 M aq. HCI (1 or 2x), dilute NaHCO 3 (1 or 2x), and brine Then, the organic phase was dried over either MgSO 4 or NaSO 4 filtered, concentrated to provide the crude product, which was either further purified or utilized without further purification.
GENERAL PROCEDURE J EEDO Coupling Procedure To a solution of the amine in THF (1.0 eq., 0.05-0.08 M, final molarity) under N, at room temperature was added the N-t-Boc protected amino acid (1.1 eq., either as a solid or in THF via cannula), followed by EEDQ (Aldrich, 1.1 The pale yellow solution was stirred at room temperature for 16-16.5 hours, then diluted with EtOAc (in a 3-5 volume multiple of the initial THF volume), and washed with 1M aq. HC1 dilute aq. NaHCO 3 and brine The organic phase was dried over either Na,SO 4 or MgSO 4 filtered, and concentrated.
II. Carboxvlic Acids GENERAL PROCEDURE II-A Ester Hydrolysis to Free Acid Ester hydrolysis to the free acid was conducted by conventional methods.
Below are two examples of such conventional de-esterification methods.
Method A: To a carboxylic ester compound in a 1:1 mixture of was added 2-5 equivalents of K,C0 3 The mixture was heated to 0 C for 0.5 to 1.5 hours until tic showed complete reaction. The reaction was cooled to room temperature and the methanol was removed on a rotary evaporator. The pH of the remaining aqueous solution was adjusted to and WO 98/28268 PCT/US97/22986 221 ethyl acetate was added to extract the product. The organic phase was then washed with saturated aqueous NaCl and dried over MgSO4. The solution was stripped free of solvent on a rotary evaporator to yield the product.
Method B: The amino acid ester was dissolved in dioxane/water to which was added LiOH eq.) that was dissolved in water such that the total solvent after addition was about 2:1 dioxane:water. The reaction mixture was stirred until reaction completion and the dioxane was removed under reduced pressure. The residue was dissolved in water and washed with ether. The layers were separated and the aqueous layer was acidified to pH 2. The aqueous layer was extracted with ethyl acetate. The ethyl acetate extracts were dried over Na2SO 4 and the solvent was removed under reduced pressure after filtration.
The residue was purified by conventional methods recrystallization).
GENERAL PROCEDURE II-B Acid Chloride Preparation acid (30 g, 0.174 mol) (Aldrich) was dissolved in dichloromethane and this solution was cooled to 0°C. DMF (0.5 mL, catalytic) was added followed by the dropwise addition of oxalyl chloride (18 mL, 0.20 mol) over a 5 minute period. The reaction was stirred for 3 h and then rotoevaporated at reduced pressure to give an oil which was placed on a high vacuum pump for 1 h to afford 3,5-difluorophenylacetyl chloride as a thin yellow oil. Other acid chlorides can be prepared in a similar manner.
GENERAL PROCEDURE II-C Schotten-Baumann Procedure chloride (from General Procedure II-B) was added dropwise to a 0°C solution of L-alanine (Aldrich) (16.7 g, 0.187 mol) in 2 N sodium hydroxide (215 mL, 0.43 mol). The reaction was stirred for 1 h at 0 C and then overnight at room temperature. The reaction was diluted with water (100 mL), then extracted with ethyl acetate (3 x 150 mL). The organic layer WO 98/28268 PCT/US97122986 222 was then washed with brine (200 mL), dried over MgSO 4 and rotoevaporated at reduced pressure to a residue. Recrystallization of the residue from ethyl acetate/hexanes afforded the desired product (34.5 g, 82% yield). Other acid chlorides may be used in this procedure to provide for intermediates useful in this invention.
GENERAL PROCEDURE II-D Reductive Amination To a solution of the arylamine in ethanol in a hydrogenation flask was added 1 equivalent of the 2-oxocarboxylic acid ester pyruvate ester), followed by 10% palladium on carbon (25 weight percent based on the arylamine). The reaction was hydrogenated at 20 psi H 2 on a Parr shaker until complete reaction was indicated by tic (30 minutes to 16 hours). The reaction mixture was then filtered through a pad of Celite 545 (available from Aldrich Chemical Company, Inc.) and stripped free of solvent on a rotary evaporator.
The crude product residue was then further purified via chromatography.
Example A Synthesis of N-(Phenylacetyl)-L-alanine Using General Procedure II-C, the title compound was prepared from phenylacetyl chloride (Aldrich) and L-alanine (Aldrich) as a solid having a melting point of 102-104 0
C.
NMR data was as follows: 'H-nmr (CDCl 3 8 9.14 (br s, 1H), 7.21-7.40 5H), 6.20 J Hz, 1H), 4.55 1H), 3.61 2H), 1.37 J 7.1 Hz, 3H).
'C-nmr (CDCl 3 8 176.0, 171.8, 134.0, 129.4, 127.5, 48.3, 43.2, 17.9.
Example B Synthesis of WO 98/28268 PCT/US97/22986 223 Using General Procedure II-C, the title compound was prepared from difluorophenylacetyl chloride (General Procedure II-B) and L-alanine (Aldrich).
NMR data was as follows: 'H-nmr (CD 3 OD): 8 8.32 (br s, 0.3H), 6.71 2H), 6.60 1H), 4.74 (br s, 1.7H), 4.16 1H), 3.36 2H), 1.19 J 7.3 Hz, 3H).
3 C-nmr (CD 3 OD): 6 175.9, 172.4, 164.4 (dd, J 13.0, 245.3 Hz), 141.1, 113.1 (dd, J 7.8, 17.1 Hz), 102.9 J 25.7 Hz), 49.5, 42.7, 17.5.
Example C Synthesis of N-(Cyclopentylacetyl)-L-phenylglycine Step A Preparation of N-(Cyclopentylacetyl)-L-phenvlglycine Methyl Ester Following General Procedure A above using cyclopentylacetic acid (Aldrich) and phenylglycine methyl ester hydrochloride (Novabiochem), the title compound was prepared as a solid having a melting point of 83-86 0 C. The reaction was monitored by tic on silica gel (Rf 0.28 in 25% ethyl acetate/hexanes) and purification was by recrystallization from ethyl acetate/hexanes.
NMR data was as follows: 'H-nmr (CDC13): 8 7.35 5H), 6.44 (bd, 1H), 5.6 1H), 3.72 3H), 2.24 (bs, 3H), 1.9-1.4 6H), 1.2-1.05 2H).
"'C-nmr (CDC1 3 6 172.3, 171.7, 136.7, 129.0, 128.6, 127.3, 56.2, 52.7, 42.5, 36.9, 32.40, 32.38, 24.8.
C
1 6
H
21
NO
3 (MW 275.35); mass spectroscopy (M+Na) 298.
Step B Preparation of N-(Cyclopentylacetyl)-L-phenvlglycine Following General Procedure II-A above using N-(cyclopentylacetyl)-Lphenylglycine methyl ester (from Step the title compound was prepared as a solid having a melting point of 155-158 0 C. The reaction was monitored by tic on silica gel (Rf 0.18 in 10% methanol/dichloromethane).
NMR data was as follows: WO 98/28268 PCTIUS97/22986 224-- 'H-nmr (CDCl 3 8 8.60 J 7.8 Hz, 1H), 7.45 (in, 5HO, 5.41 J 7.2 Hz, 2.20 3H1), 1.8-1.1 (mn, 8H)..
3 C-nmr (CDCl 3 6 172.3, 172.0, 137.5, 128.7, 128.1, 127.8, 56.2, 40.9, 36.8, 31.8, 24.5.
C
15 H1 19 N0 3 (MW 261.32); mass spectroscopy (M+Na) 284.
Example D Synthesis of N-(Cyclopentylacetyl)-L-alanine Step A Prep~aration of N-(Cyclopentylacetvl)-L-alanine Methyl Ester Following General Procedure A above using cyclopentylacetic acid (Aldrich) and L-alanine methyl ester hydrochloride (Sigma), the title compound was prepared as a solid having a melting point of 43-46*C. Purification was by recrystallization from ethyl acetate/hexanes.
NMR data was as follows: 'H-rnr (CDC1 3 8 6.38 111), 4.50 (in, lH), 3.65 3H), 2.13 (bs, 3H), 1.80-1.00 (mn (includes d at 1.30, 3H), 111-).
3 C-nmr (CDCl 3 5 173.7, 172.5, 52.1, 47.6, 42.3, 36.8, 32.15, 32.14, 18.0.
CI
1
H
19 N0 3 (MW 213.28); mass spectroscopy (MW) 214.
Step B Preparation of N-(CvclopentViacetvl)-L-alanine Following General Procedure Il-A above using N-(cyclopentylacetyl)-Lalanine methyl ester (from Step the title compound was prepared. The reaction was monitored by tlc on silica gel (R~f 0.18 in inethanol/dichloromethane).
NMR data was as follows: 'H-nr (DMSO-d 6 6 12.45 (bs, 8.12 J=7.2 Hz, LH), 4.24 (quint, J =7.2 Hz, 1H), 2.14 (in, 3H), 1.8-1.4 (in, 6H), 1.29 J 7.2 Hz, 3H), 1.2-1.0 (mn, 3H1).
3 C-nmr (DMSO-d 6 8 174.6, 171.9, 47.3, 41.1, 36.7, 31.8, 24.5, 17.2.
C
10
H
17 N0 3 (MW 199.25); mass spectroscopy (MW) N/A.
WO 98/28268 PCT/US97/22986 225 Example E Synthesis of N-(Cyclopropylacetyl)-L-alanine Step A Preparation of N-(Cyclopropylacetyl)-L-alanine Methyl Ester Following General Procedure A above using cyclopropylacetic acid (Aldrich) and L-alanine methyl ester hydrochloride (Sigma), the title compound was prepared as an oil. The reaction was monitored by tic on silica gel (Rf 0.15 in 25% ethyl acetate/hexanes) and purification was by flash column chromatography using 25% ethyl acetate/hexanes as the eluant.
NMR data was as follows: 'H-nmr (CDC 3 8 6.60 1H), 4.55 1H), 3.69 3H), 2.10 (m, 2H), 1.34 3H), 0.95 1H), 0.58 2H), 0.15 2H).
3 C-nmr (CDCI 3 8 173.7, 172.3, 52.3, 47.7, 41.0, 18.2, 6.7, 4.27, 4.22.
CHi 5
NO
3 (MW 185.22); mass spectroscopy (MH) N/A.
Step B Preparation of N-(Cyclopentylacetyl)-L-alanine Following General Procedure II-A above using N-(cyclopropylacetyl)-Lalanine methyl ester (from Step the title compound was prepared as an oil.
The reaction was monitored by tic on silica gel (Rf 0.27 in methanol/dichloromethane).
NMR data was as follows: 'H-nmr (DMSO-d 6 8 8.18 1H), 4.25 1H), 2.08 2H), 1.30 (d, 3H), 1.00 1H), 0.50 2H), 0.19 2H).
"C-nmr (DMSO-d 6 6 174.6, 171.7, 47.4, 17.3, 7.6, 4.12, 4.06.
CgH, 3
NO
3 (MW 199.25); mass spectroscopy N/A.
Example F Synthesis of N-(Cyclopropylacetyl)-L-phenylglycine Step A Preparation of N-(Cyclopropylacetvl)-L-glvcine Methyl Ester Following General Procedure A above using cyclopropylacetic acid (Aldrich) and L-phenylglycine methyl ester, the title compound was prepared as a solid having a melting point of 74-76°C. The reaction was monitored by tic WO 98/28268 PCTIUS97/22986 226 on silica gel (Rf 0.61 in 50% ethyl acetate/hexanes) and purification was by recrystallization- from ethyl acetate/hexanes.
NMR data was as follows: 'H-nmr (CDCI 3 6 7.35 5H), 6.97 (bd, J=7.2 Hz, 1H), 5.59 J=7.8 Hz, 1H), 3.71 3H), 2.17 2H), 1.05-0.95 1H), 0.62 2H), 0.20 (m, 2H).
3 C-nmr (CDCl 3 5 171.9, 174.6, 136.6, 129.0, 128.5, 127.2, 56.1, 52.7, 41.0, 6.9, 4.37, 4.33.
C,
4
H,
1
NO
3 (MW 247.30); mass spectroscopy N/A.
Step B Preparation of N-(Cvclopentvlacetyl)-L-phenvlglvcine Following General Procedure II-A above using N-(cyclopropylacetyl)-Lphenylglycine methyl ester (from Step the title compound was prepared as a solid having melting point of 152-157 0 C. The reaction was monitored by tic on silica gel (Rf 0.23 in 10% methanol/dichloromethane) and purification was by recrystallization from ethyl acetate/hexanes.
NMR data was as follows: 'H-nmr (CDCl 3 6 8.47 J 7.69 Hz, 1H), 7.35 5H), 5.34 J 7.69 Hz, 1H), 2.10 2H), 0.90 1H), 0.40 2H), 0.10 2H).
1 3 C-nmr (CDC1 3 8 172.3, 171.8, 137.6, 128.7, 56.2, 7.7,
C
13
H
1 5
NO
3 (MW 233.27); mass spectroscopy N/A.
Example H Synthesis of N-(2-Biphenyl)-D,L-alanine 2-Aminobiphenyl (2 g, 11.8 mmol, Aldrich), triethylamine (1.2 eq.) and ethyl 2-bromopropionate (1.1 eq., Aldrich) were combined and heated to with stirring. After 7 days, the mixture was diluted with chloroform and washed with water. The organic portion was dried and concentrated to yield an oil which was purified by silica gel chromatography (1:1 CHCl2/hexanes). The resulting oil was dissolved in a 1:2 mixture of water/dioxane (200 mL) and LiOH (2 eq.) was added. After 2 hours, the mixture was concentrated to yield WO 98/28268 PCTIUS97/22986 227 an oil which was dissolved in water. The aqueous solution was washed with ether then was adjusted to pH 3 with 5N HCI and extracted with ethyl acetate.
The organic portion was dried and concentrated to yield an oil which was purified by silica gel chromatography (EtOAc) to yield the title compound.
Example I Synthesis of N-(Phenyl-furazan-3-yl)-D,L-alanine Following General Procedure II-D and using 4-phenyl-furazan-3-ylamine (Maybridge) and ethyl pyruvate (Aldrich), the ethyl ester was prepared.
Following General Procedure II-A, Method B (LiOH/H 2 0/dioxane) and using the ethyl ester, the title compound was prepared.
Example L Synthesis of Acid Step A Preparation of Methyl To a solution of 3,5-difluorobenzaldehyde (Aldrich) in CH 2 Cl, (100 mL) was added ZnCl 2 (6.7 g, 21.1 mmol) to form a slurry. Trimethysilyl cyanide (21.0 g, 211.2 mmol) dissolved in CH,Cl, (100 mL) was slowly added to the slurry at 0°C. The resulting solution was stirred at room temperature for 4 h.
The reaction mixture was then diluted with water and the organic layer separated. The combined organic layers were concentrated to a residue. The residue was dissolved with MeOH (200 mL) at 0°C and anhydrous HC1 gas bubbled into the solution for 10 min. After stirring at room temperature for 18 h, the solution was concentrated to a solid. The solid was dissolved in CH,CI, HO and the aqueous portion extracted with CHCl1. The combined organics were washed with brine, dried over anhydrous MgSO 4 and concentrated to a solid (37.4 g, mp 77-78 0
C.
'H NMR (300 MHz, CDCl 3 6 6.97 (dd, J 9.6 Hz, J 1.79 Hz, 2H), 6.74 (dt, J 8.82, J 2.28 Hz, 1H), 5.14 J 4.64 Hz, 1H), 3.78 3H), 3.54 J 5.1 Hz, 1H).
WO 98/28268 PCTUS97/22986 228 Step B Preparation of Methyl Methyl (±)-3,5-difluoromandelate was separated via preparative chiral HPLC to give a white solid having a melting point of 70-71 C.
C
g
H
8 F,0 3 (MW 202.17); mass spectroscopy found (M+NH 4 220.0.
Anal. calcd for C 9 HF,0 3 C, 53.47; H, 3.99. Found: C, 53.40; H, 3.89.
Step C Preparation of S-(+)-3.5-Difluoromandelic acid A solution of methyl S-(+)-3,5-difluoromandelate (1 eq.) in 74% aqueous THF was cooled to 0 OC and treated with lithium hydroxide. After 40 minutes at 0 °C the reaction was complete by TLC. The contents were transferred to a separatory funnel and partitioned between CH 2 C1, and saturated aqueous NaHCO 3 The aqueous layer was acidified with 0.5 N NaHSO 4 and extracted thrice with ethyl acetate. The combined extracts were washed with brine, dried over NaSO 4 filtered, and concentrated to a white solid having a melting point of 119-122 The 'H NMR was consistent with known acid.
Example M Synthesis of 2-Azido-(3,5-difluorophenyl)acetic Acid Step A: To a three-necked flask equipped with a mechanical stirrer and a nitrogen inlet tube was added 3,5-difluorophenylacetic acid and THF; The reaction mixture was cooled to -78 0 C and 1.2 eq. of triethylamine was added, followed by dropwise addition of trimethylacetyl chloride (1.05 During the addition, the temperature was maintained at -78 0 C. The cold bath was then removed and replaced with an ice bath. The temperature was allowed to warm to 0°C and stirring was continued for 1 hour. The reaction mixture was then recooled to -78 0 C. To a second flask charged with THF, triphenylmethane (cat, 0.1 mole and (S)-(-)-4-benzyl-2-oxazolidione (1.1 eq.) (Aldrich) at -78°C was added an n-butyl lithium solution dropwise until an orange color persisted.
This reaction mixture was stirred at -78 0 C for 30 min. and then cannulated into the first reaction mixture. The resulting mixture was allowed to stir at -78 0 C for WO 98/28268 PCT/US97/22986 229 1 hour and then quenched with 2.2 eq. of acetic acid. The solvent was removed under reduced pressure and the residue was redissolved in dichloromethane and this solution washed with water, followed by IM potassium carbonate. The organic layer was then dried over sodium sulfate, filtered and concentrated. The residue was purified by LC 2000 chromatography, eluting with EtOAC/Hexane (15:85). The resulting oil was slurried in hexane to afford a white solid which was collected by filtration to give (S)-(-)-3-(3,5-difluorophenyacetyl)-4-benzyl-2oxazolidione.
Step B: To (S)-(-)-3-(3,5-difluorophenyacetyl)-4-benzyl-2-oxazolidione mM) in 20 mL of dry THF cooled to -78 0 C was added LiHMDS (1.05 eq.) dropwise while maintaining the temperature at -78 0 C. The reaction mixture was allowed to stir at -78 0 C for 15 min. and then a pre-cooled (-60 0 C) solution of trisyl azide (1.12 eq.) in 10 mL of THF was added. The reaction mixture was allowed to stir an additional 10 min. and then was quenched with 4.4 eq. of acetic acid. Using a warm water bath, the temperature was raised to 30-40°C for 6 hrs. The reaction mixture was then poured into a separatory funnel and extracted into dichloromethane. The organic layer was washed with bicarbonate solution, followed by brine, and then dried over sodium sulfate, filtered and solvent removed. The residue was purified by LC 2000 chromatography to afford methyl 2-azido-2-(3,5-difluorophenyl)acetate.
Step C: To a solution of methyl 2-azido-2-(3,5-difluorophenyl)acetate in
THF/H
2 0 cooled to 0°C was added 1.7 eq. of lithium hydroxide. The reaction mixture was stirred at room temperature for 3 hours and then poured into a separatory funnel. The mixture was extracted into water and washed with ether. The aqueous layer was acidified with IN HCI and extracted with ethyl acetate. The organic layer was then washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2-azido-2-(3,5-difluorophenyl)acetic acid.
WO 98/28268 PCT/US97/22986 230 Example N Synthesis of (R)-N,N'-Di-BOC-2-Hydrazinopropionic Acid Step A: To (S)-(-)-4-benzyl-2-oxazolidanone (Aldrich) in THF cooled to 50 0 C was added n-butyl lithium 1.1 eq. (1.6 M in hexane) dropwise. The reaction mixture was allowed to warm to -20 0 C and then was re-cooled to -78°C and propionyl chloride (1.1 eq) was added in one portion. The reaction mixture was allowed to stir an additional 15 min. at -78 0 C and then was allowed to warm to room temperature. The reaction was then quenched with a saturated solution of sodium bicarbonate and extracted with ethyl acetate. The organic extracts were washed with water, followed by brine and then dried over sodium sulfate, filtered and concentrated to give (S)-(-)-3-propionyl-4-benzyl-2oxazolidanone.
Step B: To a solution of (S)-(-)-3-propionyl-4-benzyl-2-oxazolidanone in THF at -78 0 C was added KHMDS (1.05 eq.) (Aldrich) dropwise. The reaction mixture was allowed to stir at -78 0 C for 30 min. and then a precooled solution of di-tert-butyl-azodicarboxylate (Aldrich) was added via a cannula. After min. 2.6 eq. of acetic acid was added. The reaction mixture was then extracted with dichloromethane and the organic layer was washed with 1M potassium phosphate. The organic layer was then dried over sodium sulfate, filtered and concentrated to give (S)-(-)-3-[(R)-N,N'-di-BOC-2-hydrazinopropionyl]-4benzyl-2-oxazolidanone.
Step C: To (S)-(-)-3-[(R)-N,N'-di-BOC-2-hydrazinopropionyl]-4-benzyl-2oxazolidanone (0.49 moles) at 0°C in 8 mL of THF and 3 mL of water was added LiOH (1.7 eq.) and HzO (3.0 eq.) and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then poured into a seraratory funnel and diluted with water. The aqueous mixture was extracted with ethyl acetate and then acidified to pH 2.0 with IN HC1 and extracted with ethyl acetate. The organic layer was then dried over sodium sulfate, filtered and WO 98/28268 PCTIUS9722986 231 solvent removed to give (R)-N,N'-di-BOC-2-hydrazinopropionic acid which was used without further purification.
Example O Synthesis of Acid Step A: Ethyl 3,5-difluorophenyl-a-oxoacetate was prepared from 1-bromo- (Aldrich) according to the procedure described in J. Org.
Chem., 45 2883-2887 (1980).
Step B: Ethyl 3,5-difluorophenyl-ac-oxoacetate was hydrolyzed using General Procedure II-A (Method B) to afford acid.
Example P Synthesis of Cyclopentyl-a-hydroxyacetic Acid The title compound (CAS No. 6053-71-0) was prepared in two steps from cyclopentylmethanal (CAS No. 872-53-7, Wiley) using the procedure described by Gibby, W. Gubler, C. J. Biochemical Medicine 1982, 27, 15-25.
Example Q Synthesis of N-(3,4-dichlorophenyl)alanine Using the procedure set forth in U.S. Patent No. 3,598,859, the disclosure of which is incorporated herein by reference in its entirety, N-(3,4dichlorophenyl)alanine was prepared. Specifically, to a solution of 3,4dichloroaniline (1 equivalent) (Aldrich) in isopropanol (about 500 mL per mole of 3,4-dichloroaniline) is added water (about 0.06 mL per mL of isopropanol) and 2-chloropropionic acid (2 equivalents) (Aldrich). This mixture is warmed to 40 0 C and sodium bicarbonate (0.25 equivalents) is added in successive portions before heating under reflux for 4-5 days. After cooling, the reaction mixture is poured into water and the unreacted 3,4-dichloroaniline is removed by filtration.
WO 98/28268 PCT/US97/22986 232 The filtrate is acidified to pH 3-4 with concentrated hydrochloric acid and the resultant precipitate is filtered, washed and dried to yield the title compound, m.p. 148-149 0
C.
Example R Synthesis of Using the procedure set forth in U.S. Patent No. 3,598,859 and Example Q above, N-(3,5-difluorophenyl)alanine was prepared using (Aldrich) and 2-chloropropionic acid (Aldrich).
Example S Synthesis of Acid Step A Synthesis of Methyl To a solution of 3,5-difluoromandelic acid (Fluorochem) in methanol was bubbled HCI gas for 10 minutes. The reaction was refluxed overnight. The mixture was then concentrated in vacuo and the residue was taken up in ethyl acetate and washed with saturated NaHCO 3 and brine. The organic layer was dried over NaSO 4 filtered, and concentrated to give the title intermediate as a white solid.
C
9
H
8 F,0 3 (MW=202.17); mass spectroscopy 202.
'H NMR (300 MHz, CDCl 3 6 7.00 (2H, d, J=6.58 Hz), 6.76 (1H, t, J=8.86 Hz), 5.16 (1H, d, J=5.29 Hz), 3.81 (3H, 3.54 (1H, d, J=5.39 Hz).
Step B Synthesis of Methyl A solution of diethylaminosulfur trifluoride (DAST) (1.1 eq) in methylene chloride was cooled to 0°C and a pre-cooled solution of methyl difluoromandelate (1 eq) in methylene chloride was added. The transfer flask was rinsed with a small portion of methylene chloride. After 15 minutes, the cooling bath was removed and the reaction mixture was stirred an additional minutes at ambient temperature. The mixture was poured over ice and the layers separated. The organic phase was washed with saturated NaHCO 3 and WO 98/28268 PCT/US97/22986 233 brine. The organic layer was dried over Na,SO 4 filtered, and concentrated.
The residue was purified via HPLC eluting with 7% ethyl acetate/hexanes providing the title intermediate as a yellow oil.
C
9
H
7
F
3 02 (MW=204.16); mass spectroscopy 204.
Anal. calcd for C 9
,HF
3 0: C, 52.95; H, 3.46. Found: C, 52.80; H, 3.73.
Step C Synthesis of a-Fluoro-3,5-difluorophenylacetic Acid Following General Procedure II-A, Method B and using methyl a-fluorothe title intermediate was prepared as a white solid having a melting point of 100-102 0
C.
C
8
HF
3 0 2 (MW 190.13); mass spectroscopy 190.
Anal. calcd for CHF 3 02: C, 50.54; H, 2.65. Found: C, 50.47; H, 2.79.
III. Cycloalkvl, Lactam, Lactone and Related Compounds 1. Cvcloalkane Derivatives Example 1-1 Synthesis of 1-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)aminodibenzosuberane Following General Procedure C above using alanine (Example B) and 1-aminodibenzosuberane, the title compound was prepared. The product was purified by chromatography (silica, MeOH/CHCI 3 followed by recrystallization from n-chlorobutane/acetonitrile.
NMR data was as follows: 'H-nmr (DMSO-d 6 6 4.53 1H), 6,37 1H).
C
26
H
24 N,0 2
F
2 (MW 434.48); mass spectroscopy (MH 434.
2. Cyclic Alcohol Derivatives WO 98/28268 PCT/US97/22986 234 Example 2-A Synthesis of 5-Amino-5,7-dihydro-6Hdibenzo[a,c]cyclohepten-6-ol Hydrochloride Step A Synthesis of 5-Oximo-5.7-dihvdro-6Hdibenzo[a.clcvclohepten-6-one A round bottom flask was charged with 5,7-dihydro-6Hdibenzo[a,c]cyclohepten-6-one (1.0 g, 4.81 mmol)(CAS# 1139-82-8, prepared as described in Tetrahedron Letters, Vol. 28, No. 23, (1987), pp 2633-2636) and butyl nitrite (0.673 ml, 5.77 mmol) (Aldrich) in Et 2 O. The solution was cooled to 0°C and treated drop-wise with a saturated solution of HCl(g)/Et 2
O.
After 5 h at 0°C the resulting precipitate was filtered, rinsed with cold Et2O and vacuum dried to give the title compound as a colorless solid.
NMR data was as follows: 'H-nmr (CDCl 3 6 7.26-7.74 8H), 3.84 2H).
C,
1 sHINO 2 (MW 237.26); mass spectroscopy 238.
Anal. Calcd for CsH,,NO 2 C, 75.93 H, 4.67 N, 5.90. Found: C, 75.67 H, 4.83 N, 5.67.
Step B- Synthesis of 5-Amino-5,7-dihvdro-6Hdibenzo[a,clcyclohepten-6-ol Hydrochloride The compound isolated above (0.489 g, 2.04 mmol) was dissolved in THF and added drop-wise to a well-stirred mixture of LAH (10.2 ml, 10.2 mmol)/THF. After heating to reflux for 25 h under N 2 atmosphere the solution was quenched and worked-up according to Fieser's method. The resulting solid was rinsed with NH 3 sat/CHCl 3 the filtrate evaporated and the title compound purified by chromatography (SiO 2 CHC1 3 C,,HiNO (MW 225.290); mass spectroscopy 226.
Anal. Calcd for C,,H, 5 NO; C, 79.97 H, 6.71 N, 6.22. Found: C, 80.19 H, 6.71 N, 5.91.
WO 9=/8268 PTU9/28 PCTIUS97/22986 235 Example 2-1 Synthesis of 1 amino-2-(S)-indanol Following General Procedure C and using alanine (Example B) and I -(R)-amino-2-(S)-indanol, the title compound was prepared.
Example 2-2 Synthesis of 1 amino-2-(R)-indanol Following the General Procedure C and using L-alanine (Example B) and I -(S)-amino-2-(R)-indanol, the title compound was prepared.
Example 2-3 Synthesis of amino-2-indanol Following General Procedure C and using alanine (Example B) and 1 -amino-2-indanol, the title compound was prepared.
Example 2-4 Synthesis of trans-2-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-i -cyclohexanol Following General Procedure C above using alanine (Example B) and trans-2-aminocyclohexanol hydrochloride (Aldrich), the title compound was prepared as a solid having a melting point of 189-191'C.
The reaction was monitored by tlc on silica gel (Rf =0.85 in 9% methanol/dichloromethane) and purification was by flash chromatography using 9% methanol/dichloromethane as the eluant.
NMR data was as follows: WO 98/28268 PCT/US97/22986 236 'H-nmr (CD 3 OD): 6 6.8-6.6 (in, 3H), 4.1 (in, J 7.2 Hz, 1H), 3.4 (in, 4H), 3.1 (in, 1H), 1.8-1.4 (in, 4H), 1.1 (in, 7H).
13 C-nmr (CD 3 OD) 6 175.4, 173.0, 113.9, 113.6, 103.9, 103.6, 74.3, 56.9, 51.4, 51.4, 50.4, 43.4, 43.3, 43.31, 36.0, 35.5, 32.9, 32.8, 26.2, 26.2, 25.9, 25.8, 18.8, 18.7.
C
1 7H 22
N
2 0 3
F
2 (MW 340.37); mass spectroscopy (MHW) 341.
Example Synthesis of 1-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino-i ,2,3,4-tetrahydro-2-naphthol Following General Procedure C and using using difluorophenylacetyl)-L-alanine (Example B) and 1 -amino-i ,2 ,3 ,4-tetrahydro-2naphthol, the title compound was prepared.
Example 2-6 Synthesis of 1-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)aminobenz[fjcycloheptan-2-oI Following General Procedure D and using alanine (Example B) and cis- 1-ainino-2-hydroxybenzosuberane (prepared using the procedure described in C. H. Senanayake et al., Tetrahedron Lett. (1995) 36(42), 7615-7618), the title compound was prepared. The reaction was monitored by tic on silica gel (Rf 0.4 in 10% inethanol/dichloroinethane) and purification was by silica gel chromatography using inethanol/dichloroinethane as the eluant.
NMR data was as follows: Mixture of cis isomers: 'H-nmr (DMSO-d 6 5 4.46 (in, 1H), 5.05 1H).
C
22
H,-
3 N,0 3
F
2 (MW 402.44); mass spectroscopy (MHW) 402.
Using the above procedure, followed by crystallization from acetonitrile gave a single isomer: WO 98/28268 PCT/US97/22986 237 'H-nmr (DMSO-d 6 6 4.46 1H), 5.03 1H).
C
2 2
H
23
N
2 0 3
F
2 (MW 402.44); mass spectroscopy (MH 402.
Example 2-7 Synthesis of 5-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]amino- 5,7-dihydro-6H-dibenzo[a,c]cyclohepten-6-ol Following General Procedure D above using L-alanine (Example B) and 5-amino-5,7-dihydro-6H-dibenzo[a,c]cyclohepten-6ol hydrochloride (Example the title compound was prepared as a colorless solid. The product was purified by flash chromatography using 98:2 CHC1 3 /MeOH.
C
26
H
24
F
2
N
2 0 3 (MW 450.48); mass spectroscopy 451.
Anal. Calcd for C 2 6
H
2 4
F
2
N
2 0 3 C, 69.32 H, 5.37 N, 6.22. Found: C, 69.02 H, 5.53, N, 6.34.
3. Cyclic Ketone Derivatives GENERAL PROCEDURE 3-A Jones Oxidation Procedure The compound to be oxidized was stirred in acetone and the Jones reagent was added in portions until the starting material was consumed. The reaction mixture was quenched with isopropanol and the mixture was filtered through Celite and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water and the organic portion was dried over sodium sulfate and then concentrated under reduced pressure. The crude product was purified by silica gel chromatography and/or recrystallization.
GENERAL PROCEDURE 3-B Swern Oxidation Procedure WO 98/28268 PCT/US97/22986 238 To a stirred mixture of oxalyl chloride (0.1.5 mL, 1.2 mmol) in 10 mL of dichloromethane cooled to -78 0 C was added DMSO (0.106 mL, 1.5 mmol) and the mixture was stirred for 10 minutes. A solution of th alcohol (0.1828 g, 0.60 mmol) in 20 mL of chloroform was added dropwise. The reaction mixture was stirred at -78 0 C for 2 hours, and then 0.5 mL (3.6 mmol) of triethylamine was added. Stirring was continued for 1 hour and then the mixture was allowed to warm to room temperature and stirring was continued at ambient temperature overnight. The mixture was then diluted with 50 mL of dichloromethane, washed with brine dried over magnesium sulfate, filtered and evaporated to dryness to give the crude product which as typically purified by column chromatography.
Example 3-1 Synthesis of 1-(S)-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)aminoindan-2-one Following General Procedure 3-A using the product from Example 2A-2, the title compound was prepared as a solid having a melting point of 221- 224°C. The reaction was monitored by tic on silica gel (Rf 0.4 in methanol/dichloromethane) and purification was by silica gel chromatography using 5% methanol/dichloromethane as the eluant, followed by recrystallization from 1-chlorobutane/acetonitrile.
NMR data was as follows: 'H-nmr (DMSO-d 6 6 1.25 3H), 4.34 1H), 5.22 1H), 8.37 1H), 8.72 1H).
C
20
H
1 8 sN0 3
F
2 (MW 372.38); mass spectroscopy 372.34.
Example 3-2 Synthesis of 2-(N'-(Phenylacetyl)-L-alaninyl)aminocyclohexan-l-one WO 98/28268 PCTIUS97/22986 239 Following General Procedure 3-B3 above using 2-(N'-(phenylacetyl)-Lalaninyl)-amino-1-cyclohexanol (Example the title compound was prepared as a solid having a melting point of 150-157'C. Purification was by silica gel chromatography using 3% methanol/ dichioromethane as the eluant.
NMR data was as follows: 'H-nmr (CDCl 3 6 7.24-7.40 (in, 5H), 6.7-6.9 (in, 1H), 6.1 (mn, LH), (in, 1H), 4.40 (mn, 1H), 3.61 2H), 3.59 2H), 2.55 (in, 2H), 2.38 (in, iHO, 2.13 (in, 11HO, 1.72-1,92 (in, 2H), 1.63 (in, 11H), 1.32 (mn, 4H).
1 3 C-nmr (CDCl 3 b 207.3, 171.75, 171.69, 170.8, 170.6, 134.6, 134.5, 129.3, 129.2, 128.9, 127.3, 127.2, 57.93, 57.88, 48.8, 48.7, 43.5, 40.99, 40.96, 35.0, 34.8, 27.8, 23.96, 23.92, 18.7, 18.4.
C
17
H
2 7N 3 0 3 (MW 302.38).
Example 3-3 Synthesis of 5-[N'-(3,5-Difluorophenylacetyl)-L-alaninyllamino- 5,7-dihydro-611-dibenzo[a,clcyclohepten-6-one Using General Procedure 3-A and using 5-[N'-(3,5-Difluorophenylacetyl)- L-alaninyl]-amino-5 ,7-dihydro-6H-dibenzo[a cyclohepten-6-ol (Example 2-7), the title compound was prepared. The product was purified by flash chromatography using 97:3 CHCI 3 /MeOH.
NMR data was as follows: 'H-ninr (CDCl 3 6 7.61-7.16 (in, 8H1), 6.78 (in, 2H), 6.69 (in, 1H), 6.31 and 6.21 (two d, 1H), 5.51 1H), 4.67 3.66 (in, 2H), 3.49 (two s, 2H1), 1.49 and 1.38 (two m, 3H).
C
26
H
22
F
2
N
2 0 3 (MW 448.46); mass spectroscopy (MH 449.
Anal. Calcd for C, 26
H
22
F
2
N
2 0 3 C, 69.63 H, 4.94 N, 6.25. Found: C, 69.67 H, 4.85, N, 6.23.
WO W828268 PCTIUS97/22986 240 Example 3-4 Synthesis of 1-(N aminobenzllfjcycloheptan-2-one Following General Procedure 3-A and using 1-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)-aminobenz[flcycloheptan-2-ol (Example the title compound was prepared.
4. Lactones Example 4-1 Synthesis of 3-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-y-butyrolactone Following General Procedure A above using N-(3 L-alanine (Example B) and ai-amino--y-butyrolactone hydrobromide (Aldrich), the title compound was prepared as a solid having a melting point of 174- 1 77'C. The reaction was monitored by tic on silica gel (Rf 0.52 in methanol/dichioromethane) and purification was by silica gel chromatography.
NMR data was as follows: 'H-nr (CDCl 3 8 8.4 (in, 2H), 7.1 (in, 1H); 7.0 (in, 2H); 4.6 (in, 1H1); 4.4 (in, 2H); 3.52 2H); 2.2 (in, 2H); 1.22 (in, 3H).
3 C*nmr (CDCl 3 6 175.6, 172.7, 169.2, 112.8, 106.6, 102.2, 65.6, 48.5, 48.3, 41.6, 28.6, 18.7.
C
15
H
16
F
2
N
2 0 4 (MW 326); mass spectroscopy (MW) 327.
Example 4-2 Synthesis of 3-(N '-(3,4-dichlorophenyl)-D,L-alaninyl)amino-,y-butyrolactone Following General Procedure A and using N-(3,4-dichlorophenyl)-D.Lalanine (Example A) and cc-amino-y-butyrolactone hydrobromide (Aldrich), the title compound was prepared. The reaction was monitored by tic on silica gel (Rf 0. 19 in 60% EtOAc/hexane) and purification was by silica gel chromatography using 60% EtOAc/hexanes as the eluent.
WO 98=8268 PCT/US97/22986 241 NMR data was as follows: 'H-nmr (CDC1 3 8 1.56 J 7 Hz, 3H), 2.0-2.15 (in, 1H), 2.75-2.9 (mn, 1H), 3.75-3.90 (in, 1H), 4.0 (brs, 1H), 4.2-4.35 (mn, LH), 4.45 J 7, 1H), 4.5-4.7 (mn, 1H), 6.4-6.5 (mn, 1H), 6.67 J =3 Hz, 1H), 7.0-7.1 (in, 1H), 7.2-7.3 (mn, 1H).
3 C-nmr (CDCI 3 6 20.0, 30.7, 49.4, 55., 66.5, 113.7, 115.5, 112.8, 131.5, 133.7, 146.3, 174.5, 175.5.
C
13
HI
4 C1 1
N
2 0 3 (MW 317.17); mass spectroscopy 317.
Example 4-3 Synthesis of 4-(N '-(Cyclopentylacetyl)-L-alaninyl)amino- 1 ,1-dimethyl-3-isochromanone Following General Procedure A above using N-(cyclopentylacetyl)-L-alanine and 4-amino-l,1-dimethyl-3-isochroinanone, the title compound could be prepared.
Example 4-4 Synthesis of 4-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino- 1,1 -dimethyl-3-isochronianone Following General Procedure A above using N-(3 alanine and 4-amino- 1,1-dimethyl-3-isochroinanone, the title compound could be prepared.
Lactams GENERAL PROCEDURE N-Alkylation of Lactams To a stirred solution of a BOC-protected ax-aininocaprolactain (6.87 g, minol) in DMF (150 mL) was added in portions 97% NaH (1.08g, 45 minol).
Bubbling occured immediately and followed by heavy precipitation. After min., benzyl bromide (3.93 mL, 33 iniol) was added. The precipitate dissolved WO 98/28268 PCT/US97/22986 242 quickly and in about 10 min. a clear solution was obtained. The reaction mixture was stirred overnight and then evaporated as completely as possible on a rotovap at 30 0 C. Ethyl acetate (100 mL) was added to the residue and this mixture was washed with water, brine, and dried over magnesium sulfate. After filtration and concentration, a thick liquid (10 g) was obtained which was then chromatographed over silica gel with 1:3 ethyl acetate/hexane as the eluant to provide 5.51 g of the N-benzylated product as an oil. Other lactams and alkylating agents may be used in this procedure to obtain a wide variety of Nalkylated lactams. Various bases, such as LiN(SiMe 3 may also be employed.
GENERAL PROCEDURE BOC Removal Procedure The BOC-protected compound in a 1:1-2:1 mixture of CH,Cl, and trifluoroacetic acid was stirred until tic indicated complete conversion, typically 2 hours. The solution was then stripped to dryness and the residue was taken up in ethyl acetate or CH 2 C12. The solution was washed with saturated aqueous NaHCO 3 and the aqueous phase was adjusted to a basic pH, then extracted with ethyl acetate or CH 2 The organic phase was washed with saturated aqueous NaCl and dried over MgSO 4 The solution was stripped free of solvent on a rotary evaporator to yield the product.
GENERAL PROCEDURE Synthesis of ao-Aminolactams The Schmidt reaction was conducted on 4-ethylcyclohexanone using hydroxyamine sulfonic acid as described in Olah, Org. Synth. Collective, Vol.
VII, page 254, to provide 5-ethylcaprolactam in 76% yield. Using the procedure described in Watthey, et al., J. Med. Chem., 1985, 28, 1511-1516, this lactam was then dichlorinated with PC1, at the alpha position and reduced by hydrogenation to provide four isomeric monochlorides (two racemic mixtures).
The two racemic mixtures were separated from each other by column chromatography using silica gel and each racemic mixture was reacted with WO 98/28268 PCT/US97/22986 243 sodium azide to yield the corresponding azide which was hydrogenated to provide the corresponding a-aminolactams. Other cycloalkanones may be employed in this procedure to provide a wide variety of a-aminolactams. In some cases, such as when preparing the 9-membered ring c-aminolactam, longer reaction times, higher reaction temperatures and an excess of sodium azide may be required. For example, the 9-membered ring a-aminolactam required equivalents of sodium azide, a reaction temperature of 120 0 C and a reaction time of 4 days. Such conditions can be readily determined by those of ordinary skill in the art.
GENERAL PROCEDURE Synthesis of 4-Amino-1,2,3, 4 -tetrahydroisoquinoline-3-ones The 4-amino-1,2,3,4-tetrahydroisoquinoline-3-one derivatives employed in this invention can be prepared by the following art-recognized procedures. The conditions for these reactions are further described in D. Ben-Ishai, et al., Tetrahedron, 43, 439-450 (1987). The following intermediates were prepared via this procedure: 3-amino-1,2,3,4-tetrahydroisoquinolin-3-one 4-amino-7-benzyl-1,2,3,4-tetrahydroisoquinolin-3-one 4-amino- 1 -phenyl- 1,2,3,4-tetrahydroisoquinolin-3-one cis and trans-4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one 4-amino-2-phenethyl- 1,2,3,4-tetrahydroisoquinolin-3-one 4-amino-2-methyl-1,2,3,4-tetrahydroisoquinolin-3-one 9-amino(fluoren-1-yl)glycine 8-lactam- 1,2,3,4-tetrahydroisoquinolin-3-one.
Step A Preparation of N-Bismethoxvcarbonvlaminoacetic Acid: To one mole equivalent of glyoxylic acid in 2 liters of ethanol-free chloroform was added two mole equivalents of methyl carbamate and 0.1 mole equivalent of naphthalene sulfonic acid. The reaction mixture was then brought to a reflux for 6 hours. Water was removed using an inverse Dean Stark trap. The reaction was then cooled and the product filtered and washed with chloroform. The WO 98/28268 PCTIUS97/22986 244 white solid was recrystallized from ethyl acetate/hexanes to give a white powder in 65% yield.
Step B Coupling Procedure: To 0.0291 moles of Nbismethoxycarbonylaminoacetic acid (or the appropriate carboxcyclic acid) in 200 mL of THF was added one mole equivalent of EDC*HCI, a benzylamine, HOBT, and diisopropylethylamine. The reaction was allowed to stir at room temperature for 18 hours and then poured into a separatory funnel and extracted into ethyl acetate. The ethyl acetate solution was washed with 1 molar K,CO 3 and then 1 molar HC1. The organic layer was dried over Na 2
SO
4 filtered and solvent removed to give the crystalline benzylamide of Nbismethoxycarbonylaminoacetic acid. This material was used without further purification. Typical yields range from 40 Step C Cyclization Procedure: The benzylamide of Nbismethoxycarbonylaminoacetic acid (0.008 moles) was dissolved in 75 mL of methanesulfonic acid and allowed to stir over night at room temperature. The reaction mixture was poured over ice and extracted into ethyl acetate. The ethyl acetate extract was washed with 1 molar KCO 3 and then 1 N HC1. The organic layer was dried over Na 2
SO
4 filtered and the solvent removed to give the crystalline 4-methoxycarbonylamino-1,2,3,4-tetrahydroisoquinoline-3-one in yield. This material was used without further purification.
Step D Removal of the Methoxvoxycarbonvl Group (MOC): To the 4methoxycarbonylamino-1,2,3,4-tetrahydroisoquinoline-3-one (3.4 mmoles) in mL of acetonitrile was added 2 mole equivalents of trimethylsilyliodide (TMSI).
The reaction mixture was heated to 50-80 0 C for 3 hrs and then cooled and poured into a seperatory funnel. The reaction mixture was diluted with ethyl acetate and washed with 1 molar K 2
CO
3 and then with 5% NaHSO 3 The organic layer was dried over NaSO and filtered. The solvent was removed WO 98/28268 PCT1US97/22986 245 under reduced pressure to give the 4-amino-l,2,3, 4 -tetrahydroisoquinoline-3-one derivative. Typical yields range from 50-87%.
Step E Alternative Procedure for Removal of the Methoxvoxycarbonvl Group: To 3.8 mmoles of the MOC-protected compound was added 10 mL of HBr in acetic acid and this reaction mixture was heated to 60 0 C for 3 hrs.
The mixture was then cooled and hexanes were added. The hexanes layer was decanted off and the residue as placed under reduced pressure to give a tan solid. This solid was slurried in ether and filtered to give the 4-amino-1,2,3,4tetrahydroisoquinoline-3-one hydrobromide salt. Typical yields range from 57- 88%.
Example Synthesis of 3-Amino-l,2,3,4-tetrahydroquinolin-2-one Step A: Sodium (0.30g, 110M%) was added to anhydrous ethanol (45 mL) and the reaction mixture was stirred until homogenous. Diethyl Nacetylaminomalonate (2.51 g, 100 was added in one portion and this mixture was stirred for 1 h. 2-Nitrobenzyl bromide (2.5g, 100M%) was then added in one portion and the reaction mixture was stirred for 3 h. The reaction was poured into water and extracted with ethyl acetate (3x) and then backwashed with water (3x) and brine Treatment with MgSO 4 rotoevaporation, and chromotography (30% EtOAc/hexanes) yielded diethyl Nacetylamino-2-nitrobenzylmalonate in 82% yield.
Step B: Diethyl N-acetylamino-2-nitrobenzylmalonate (1g, 100M%) was dissolved in a minimum amount of EtOH. Pd/C 0.05g) was added and the reaction mixture was subjected to 50 psi of H 2 for 3 hours. The reaction was then filtered thru a pad of celite. Additional EtOH (25mL) and TsOH (catalytic amount, 0.01g) were added and this mixture was refluxed for 2 hours.
The reaction was rotoevaporated to a residue and then partitioned between water and ethyl acetate. The Water layer was extracted with ethyl acetate (3x) and the WO 98/28268 PCT/US97/22986 246 combined ethyl acetate extracts were washed with water (3x) and then brine Treatment with MgSO 4 and rotoevaporation yielded pure 3-(Nacetylamino)-3-carboethoxy-1,2,3,4-tetrahydroquinolin-2-one (89% yield).
Step C: 3-(N-Acetylamino)-3-carboethoxy- 1,2,3,4-tetrahydroquinolin-2-one (0.75 g, 100M%) was suspended in 6N HCI (25 mL) and the mixture was heated to 100 0 C for 3 hours. The reaction was cooled, rotoevaporated to a residue and then partitioned between water and ethyl acetate. The water was extracted with ethyl acetate (3x) and the combined ethyl acetate extracts were then washed with water (3x) and then brine Treatment with MgSO, followed by rotoevaporation yielded 3-(R,S)-amino-1,2,3,4-tetrahydroquinolin-2one (72% yield).
Example Synthesis of 4-Amino-l-(pyrid-4-yl)-l,2,3,4-tetrahydroisoquinolin-3-one Step A: To a solution of 4-cyanopyridine (Aldrich) (0.150 moles) in 300 mL of dry ether was added 1.1 eq. of phenylmagnesium bromide (Aldrich) dropwise. The reaction was refluxed for 2 hours and then stirred overnight at room temperature. Sodium borohydride (1.0 eq.) was added dropwise as a solution in 200 mL of methanol (CAUTION very exothermic). The reaction was then heated to reflux for 6 hours, cooled and quenched with a saturated solution of ammonium chloride. The solution was decanted from the salt in the reaction mixture and acidified with IN HCI. After washing the aqueous layer with ethyl acetate, the pH of aqueous layer was adjusted to about 9.0 with IN sodium hydroxide (cold). The aqueous layer was then extracted with ethyl acetate and the organic extracts washed with brine, dried over NaSO 4 filtered and concentrated to give 4-pyridyl-ot-benzyl amine as a thick yellow oil.
Step B: Following General Procedure 5-D and using 4-pyridyl-a-benzyl amine, the title compound was prepared.
WO 98/28268 PCT/US97/22986 247 Example Synthesis of 4-Amino- -(pyrid-2-yl)-l, 2 3 4 -tetrahydroisoquinolin-3-one Step A: 2-Pyridyl-a-benzyl amine was prepared by substituting 2cyanopyridine (Aldrich) for 4-cyanopyridine in the procedure described in Example Step B: Following General Procedure 5-D and using 4-pyridyl-a-benzyl amine, the title compound was prepared.
Example Synthesis of 4 -Amino-l-(pyrid-3-yl)-l,2,3,4-tetrahydroisoquinolin-3-one Step A: Following the procedure described in J. Med. Chem., 1982, 1248, and using 3-benzoyl-pyridine (Aldrich), 3-pyridyl-a-benzyl amine was prepared.
Step B: Following General Procedure 5-D and using 3-pyridyl-a-benzyl amine, the title compound was prepared.
Example Synthesis of 4-Amino-7-benzyl-l, 2 ,3,4-tetrahydroisoquinolin-3-one Step A: To a Parr bottle containing 3-benzoylbenzoic acid (0.044 moles) (Aldrich) in 150 mL of ethyl acetate and 4.5 mL of concentrated HSO0 4 was added 10 grams of 5% Pd/C. The mixture was hydrogenated on a Parr apparatus under hydrogen (45 psi) overnight. The reaction mixture was then filtered through Hyflo, washing with ethyl acetate. The filterate was dried over Na,SO 4 filtered and concentrated to give an oil. The oil was slurried in hexane and the resulting white solid was collected by filtration to afford 3benzylbenzoic acid, which was used without further purification.
WO 98/28268 PCTIUS97/22986 248 Step B: To the product from Step A (0.0119 moles) was added 150 mL of
CH
2 Cl 2 one drop of DMF, 10 mL of oxalyl chloride, and the mixture was stirred at room temperature for 3 hours. After cooling to 10°C, 30 mL of (exothermic) was added and the mixture was stirred for 30 min. The reaction mixture was then concentrated and the resulting residue diluted with ethyl acetate. The organic layer was washed with IN NaOH, brine, dried over Na,S0 4 and concentrated to give the 3-(benzyl)benzamide as a white solid, which was used without further purification.
Step C: To a solution of 3-(benzyl)benzamide (.0094 moles) from Step B in 70 of toluene was added 8 mL of Red-Al® (65+ wt. solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene, Aldrich) (CAUTION reaction very exothermic). The reaction mixture was then heated at 60 0 C for 2 hours and then poured over ice. The resulting mixture was extracted with ethyl acetate and the combined extracts were washed with water and brine. The organic layer was extracted with IN HCI and the aqueous layer washed with ethyl acetate. The pH of the aqueous layer was then adjusted to about 9.0 with IN NaOH and extracted with ethyl acetate. The organic extracts were washed with water and brine and then concentrated to give 3-(benzyl)benzyl amine.
Step D: Following General Procedure 5-D and using 3-(benzyl)benzyl amine, the title compound was prepared.
Example Synthesis of 4-Amino-6-phenyl-l,2,3,4-tetrahydroisoquinolin-3-one Step A: To a solution of 4-biphenylcarboxamide (Aldrich) (0.025 mole) in 150 mL of THF cooled to 10 0 C was added a solution of 1.5 eq of LAH (1M in THF) dropwise. The reaction mixture turned from a white slurry to a green homogenous solution and then to a yellow homogeneous solution. The reaction was then quenched with 2.5 mL of IN NaOH. The mixture was then filtered through Hyflo and extracted with ethyl acetate. The organic layer was then WO 98/28268 PCT/US97/22986 249 washed with IN HC1. The pH of the resulting aqueous layer was adjusted to about 9 with IN NaOH and extracted with ethyl acetate. The organic extracts were washed with water and brine, and then dried over NaSO 4 filtered and concentrated to give 4-(phenyl)benzyl amine as a white solid.
Step B: Following General Procedure 5-D and using 4-(phenyl)benzyl amine, the title compound was prepared.
Example Synthesis of cis- and trans-4-Amino-l-phenyl-l,2,3,4-tetrahydroisoquinolin-3-one Step A: Following General Procedure 5-D and using a-phenylbenzylamine (Aldrich), 4-amino-l-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one was prepared.
Step B: To a solution of 4-amino-l-phenyl-1,2,3,4-tetrahydroisoquinolin-3one (0.00158 moles) from Step A in 20 mL of CH 2
CI
2 was added 2.0 eq. of triethylamine and Boc anhydride (1.1 The reaction was stirred overnight at room temperature and then concentrated. The residue was diluted with ethyl acetate and water. The pH of the aqueous layer was adjusted to 3.0 with sodium bisulfate and the layers were separated. The organic layer was dried over Na 2
SO
4 filtered and concentrated. The residue was purified by LC 2000, eluting with ethyl acetate/hexanes (70:30) to give a white solid containing a 1:1 mixture of cis- and trans-4-(N-Boc-amino)-1-phenyl-1,2,3,4tetrahydroisoquinolin-3-one isomers. This mixture was recrystallized from ethyl acetate to give the pure trans isomer and a cis isomer-enriched mixture of cis and trans isomers. This mixture was recrystallized again from ethyl acetate/hexanees (70:30) to give the pure cis isomer.
Step C: The cis isomer and the trans isomer from Step B were separately deprotected using General Procedure 8-J to give cis-4-amino-l-phenyl-1,2,3,4tetrahydroisoquinolin-3-one and trans-4-amino-l -phenyl-1,2,3,4tetrahydroisoquinolin-3-one.
WO 98/28268 PCT/US97/22986 250 Example Synthesis of 4-Amino-7-phenyl-l,2,3,4-tetrahydroisoquinolin-3-one Step A: To a solution of 1-bromo-3-phenylbenzene (Aldrich) (0.0858 moles) in 300 mL of dry THF cooled to -78*C was added tert-butyl lithium (2 eq.) (1.7M in hexane) dropwise. The reaction mixture was stirred for 40 min. at -78 0 C and then quenched with 2 eq. of DMF (13.24 mL). The resulting mixture was stirred for 20 min. and then poured into a separatory funnel and extracted with CH,Cl,. The organic extracts were washed with water, dried over Na 2
SO
4 filtered and concentrated to give a brown oil. This oil was purified by LC 2000 chromatography, eluting with ethyl acetate/hexanes (5:95) to give 3biphenylcarboxaldehyde.
Step B: To a solution of 3-biphenylcarboxaldehyde (0.011 eq.) in 30 mL of methanol was added 10 eq. of 7N NH 3 /MeOH and NaCNBH 4 (2 A yellow gum precipitated from solution. The solution was then heated at 60 0 C until gum dissolved and the solution was stirred at room temperature overnight. The reaction mixture was then concentrated and the resulting residue diluted with ice water and ethyl acetate. The organic layer was then washed with brine and extracted with 5N HC1. The pH of the aqueous layer was then adjusted to 12 and the aqueous layer was extracted with cold ethyl acetate. The organic layer was dried over Na 2
SO
4 filtered and concentrated to give 3-(phenyl)benzyl amine as an oil.
Step C: Following General Procedure 5-D and using 3-(phenyl)benzyl amine, the title compound was prepared.
Example Synthesis of 4-Amino-l-benzyl-1,2,3,4-tetrahydroisoquinolin-3-one Step A: To a solution of benzoyl chloride (0.123 moles) (Aldrich) in 600 mL of CH,CI, was added 2.0 eq. of phenethylamine (Aldrich) dropwise. The WO 98/28268 PCT/US972986 251 reaction mixture was stirred at room temperature for 3 hours and then poured into a separatory and extracted with CH,CI,. The organic extracts were washed with water and IN HC1, and then dried over NaSO 4 filtered and concentrated to give N-phenethyl benzamide.
Step B: Reduction of N-phenethyl benzamide using the procedure of Example 5-E, Step C afforded N-benzyl-N-phenethylamine as an oil.
Step C: Following General Procedure 5-D and using N-benzyl-Nphenethylamine, the title compound was prepared.
Example Synthesis of 3-Amino-l-methyl-2-indolinone Monohydrochloride Steo A: (2,3-Dihydro-l-methyl-2-oxo-lH-indol-3-yl)carbamic acid methyl ester (CAS No. 110599-56-9) was prepared using the procedure described in Ben-Ishai, Sataty, Peled, Goldshare, R. Tetrahedron 1987, 43, 439- 450. The starting materials for this preparation were N-methylaniline (CAS# 100-61-8, Eastman Kodak glyoxylic acid (CAS# 298-12-4, Aldrich), and methyl carbamate (CAS# 598-55-0, Aldrich).
Step B: The product from Step A (333.5 mg) in 31% HBr in AcOH mL) was heated to 50-60 0 C for 2 hours. The resulting orange solution was concentrated to a thick orange oil which was dissolved in EtOAc (15 mL) and the product extracted into 1 M aq. HCI (10 mL). The aqueous acid was neutralized with aq. NaHCO 3 and the product extracted into CH,CI, (10 x mL). HCI (gas) was passed through the combined CH 2 C1, extracts to form a purple solution. The solution was concentrated to provide the title compound (262.8 mg) as a purple solid.
WO 98/28268 PCT/US97/22986 252 Example Synthesis of 3-Amino-l-methyl-4-phenyl-3,4-trans-dihydrocarbostyril/Tin Complex Step A: Synthesis of 4-Phenyl-3,4-dihydrocarbostyril 4-Phenyl-3,4-dihydrocarbostyril (CAS# 4888-33-9) was prepared in two steps using the procedure described by Conley, R. Knopka, W. N. J. Org.
Chem. 1964, 29, 496-497. The starting materials for this preparation were cinnamoyl chloride (Aldrich) and aniline (Aldrich). The title compound was purified by flash chromatography eluting with CH 2 Cl 2 /EtOAc Step B: Synthesis of 1-Methyl-4-phenyl-3,4-dihydrocarbostyril To a suspension of NaH (1.2 eq., 0.537 g of 60% dispersion in mineral oil) in THF (50 mL) under N 2 at 0°C was added the product from Step A (1.0 eq., 2.50 g) in THF (50 mL) via cannula over a period of 5 minutes. The resulting pale yellow mixture was stirred at 0°C for 10 minutes, then Mel (2.0 eq., 1.39 mL) was added. The opaque yellow mixture was allowed to slowly (ice bath not removed) warm to ambient temperature with stirring for 15 hours. 1M Aq.
HCI (50 mL) and EtOAc (250 mL) were added and the phases partitioned. The organic phase was washed with dilute NaHCO 3 (1 x 100 mL), brine (1 x 100 mL), then dried over MgSO 4 filtered, concentrated, and the residue purified by flash chromatography eluting with CH 2
CI
2 /EtOAc (19:1 gradient to 15:1) to provide 1-methyl-4-phenyl-3,4-dihydrocarbostyril.
Step C: Synthesis of 3-Azido-l-methyl-4-phenyl-3,4-transdihydrocarbostyril Following General Procedure 8-K, 3-azido-l-methyl-4-phenyl-3,4-transdihydrocarbostyril was prepared as a white solid. The product was purified by flash chromatography eluting with CH 2 Cl2/hexanes/EtOAc 15:15:1.
Selected 'H-NMR data for the title compound (CDCI 3 5 4.46 1H, J 10.57 Hz), 4.18 1H, J 10.63 Hz).
WO 98/28268 PCT/US97/22986 253 Step D: Synthesis of 3-Amino-1-methyl-4-phenyl-3,4-transdihydrocarbostyrilTin Complex To a mixture of SnCl2 (350.7 mg) in MeOH (7 mL) under N, at 0 0 C was added the product from Step C (257.4 mg) in MeOH/THF (5 mL/5 mL) via cannula over a period of 1 minute. The cooling bath was removed the solution allowed to warm to ambient temperature for 8 hours (No starting material by TLC). The solution was concentrated to a yellow foam, THF (10 mL) was added and the mixture was re-concentrated and used without further purification.
Example Synthesis of 3-Amino- 1-methyl-4-phenyl-3,4-cis-dihydrocarbostyril Step A: Synthesis of 3-Amino-1-methyl-4-phenyl-3,4-transdihydrocarbostyril 3-Amino- 1 -methyl-4-phenyl-3,4-trans-dihydrocarbostyril was prepared following General Procedure 8-F using 3-azido-1-methyl-4-phenyl-3,4-transdihydrocarbostyril from Example 5-K, Step C. The product was purified by L.C. 2000 eluting with EtOAc/hexanes to yield a white solid.
Selected 'H-NMR data for the title compound (CDCl 3 8 4.03 1 H, J 12.8 Hz), 3.92 1H, J 12.7 Hz).
Step B: Synthesis of 3-(4-Chlorobenzylimine)-1-methyl-4-phenyl- 3,4-trans-dihydrocarbostyril To a solution of the product from Step A (1 eq., 239.6 mg) in CH,C1, mL) under N, at ambient temperature was added 4-chlorobenzaldehyde (1.05 eq., 140 mg, Aldrich), Et 3 N (1.4 eq., 185 mL), and MgSO 4 (3.6 eq., 411 mg).
The resultant mixture was stirred at room temperature for 73 hours. The solids were removed by filtration through a plug of Celite, rinsing with CH,CI,, and the filtrate concentrated to provide 3-(4-chlorobenzylimine)-1-methyl-4-phenyl- 3,4-trans-dihydrocarbostyril as a thick white foam.
Step C: Synthesis of 3-Amino-1-methyl-4-phenyl-3,4-cisdihydrocarbostyril WO 98/28268 PCT1US97t22986 254 To a solution of diisopropylamine (1.05 eq., 0.132 mL) in THF (5 mL) under N, at -78 0 C was added a solution of n-BuLi (1.05 eq., 0.588 mL of a 1.6 M solution in hexanes) and the result solution was stirred for 30 minutes. To this solution was added the product from Step B (1.0 eq., 336 mg) in THF (2 mL) via cannula. The solution was allowed to warm to 0°C, then quenched with 1 M aq. HCI (3 mL) and allowed to warm to room temperature with stirring overnight. The product was extracted into H,O and washed with EtOAc (1 then the aqueous acid was basified with 1 M aq. K2CO 3 and the product extracted into EtOAc. The EtOAc extract was dried over Na 2
SO
4 filtered, and concentrated to give 3-amino--methyl-4-phenyl-3,4-cis-dihydrocarbostyril.
Selected 'H-NMR data for the title compound (CDCI 3 8 4.31 1H, J 6.6 Hz).
Example Synthesis of 3-Amino-l-tert-butoxycarbonyl-4-phenyl- 3,4-trans-dihydrocarbostyril/Tin Complex Step A: Synthesis of 1-tert-Butoxycarbonyl-4-phenyl-3,4dihydrocarbostyril 1-tert-Butoxycarbonyl-4-phenyl-3,4-dihydrocarbostyril was prepared from the product of Example 5-K, Step A (CAS# 4888-33-9) by the Boc procedure for aryl amides described by Grehn, Gunnarsson, Ragnarsson, U. Acta Chemica Scandinavica B 1986, 40, 745-750; employing (Boc),O (Aldrich) and catalytic DMAP (Aldrich) in acetonitrile. The product was purified by flash chromatography eluting with CH,Cl gradient to CH 2 C1,/EtOAc (19:1) and isolated as a pale yellow oil.
Step B Synthesis of 3-Azido-l-tert-butoxycarbonyl-4-phenyl-3,4trans-dihydrocarbostyril Following General Procedure 8-K using the product from Step A, the title compound was prepared as a 12.4:1 mixture of trans/cis isomers which were separated by flash chromatography eluting with hexanes/EtO (6:1 gradient to WO 98/28268 PCTIUS97/22986 255 4:1) in the first column and hexanes/EtOAc (12:1) in a second column. The pure trans isomer was used in Step C.
Selected 'H-NMR data for the title compound (CDC13): 8 4.45 1H, J 11.1 Hz), 4.24 1H, J 11.2 Hz).
Step C: Synthesis of 3-Amino-l-tert-butoxycarbonyl-4-phenyl-3,4trans-dihydrocarbostyril/Tin Complex To a mixture of SnCl, (450.6 mg) in MeOH (9 mL) under N, at 0°C was added the product from Part D (433.0 mg) in MeOH (15 mL) via cannula over a period of 1 minute. The cooling bath was removed the solution allowed to warm to ambient temperature for 17 hours. The solution was concentrated to an amorphous yellow solid and used without further purification.
Example Synthesis of (S)-3-Amino-l-benzyl-6-valerolactam Step A: Synthesis of L-(+)-Ornithine Methyl Ester Hydrochloride Into a stirred suspension of L-(+)-ornithine hydrochloride (Aldrich) in methanol was bubbled anhydrous hydrochloric acid gas until the solution was saturated. The reaction mixture was capped with a rubber septum and stirring was continued overnight at room temperature. The solvent was then stripped under reduced pressure and the residue triturated with ether. The resulting solid was dried under reduced pressure to afford L-(+)-ornithine methyl ester hydrochloride as a white solid (97% yield).
Step B: Synthesis of (S)-3-Amino-&-valerolactam Sodium spheres in oil (2.0 eq.) (Aldrich) were washed with hexanes (2x) and methanol (2.3 mL/mmol) was slowly added. The reaction mixture was stirred under nitrogen until the sodium dissolved and then L-(+)-ornithine methyl ester hydrochloride (1 eq.) in methanol (2.3 mL/mmol) was added dropwise.
The reaction mixture was stirred for 16 hours and then diluted with diethyl ether mL/mmol) and filtered to remove the solids. The solvent was then removed WO 98/28268 PCTIUS97/22986 256 under reduced pressure and the residue was heated at 70 0 C for 3 hours under reduced pressure. The residue was then triturated with dichloromethane/ether, the solvent decanted and the resulting residue dried under reduced pressure to afford (S)-3-amino-5-valerolactam (44% yield).
Step C: Synthesis of (S)-3-Amino-6-valerolactam (1 eq.) was dissolved in dioxane and the solution was chilled to 0°C. BOC-anhydride (1.3 eq.) was added and the ice bath was removed allowing the solution to come to room temperature and stirring was continued for 16 hours. The solution was rotory evaporated to afford N-Boc-(S)-3-amino-6-valerolactam.
Step D: Synthesis of Following General Procedure 5-A and using valerolactam and benzyl bromide provided N-Boc-(S)-3-amino-1-benzyl-6valerolactam. Removal of the Boc group using General Procedure 5-B afford the title compuound.
Example Synthesis of 4-Amino-2-aza-2-benzyl-3-oxobicyclo[3.2.1]octane Hydrochloride Step A: Synthesis of 2-Aza-3-oxobicyclo[3.2.1]octane and 3-Aza-2oxobicyclo[3.2.1]octane (9:1 Mixture) To (+)-norcamphor (Aldrich) in 1 mL/mmole of acetic acid was added 1.5 eq. of hydroylamine-O-sulfonic acid. The reaction mixture was heated to reflux under nitrogen for 1 hour and then saturated sodium carbonate and dilute sodium hydroxide were added. The resulting mixture was extracted with dichloromethane and the organic extracts washed with brine, dried over sodium sulfate, and the solvent removed under reduced pressure. Purification of the residue by column chromatography afforded a 9:1 mixture of 2-aza-3oxobicyclo[3.2.1]octane and 3-aza-2-oxobicyclo[3.2.1]octane.
WO 98/28268 PCT/US97/22986 257 Step B: Synthesis of 2-Aza-2-benzyl-3-oxobicyclo[3.2.1]octane Following General Procedure 5-A and using the product for Step A and benzyl bromide, 2-aza-2-benzyl-3-oxobicyclo[3.2.1 ]octane was prepared.
Step C: Synthesis of 2-Aza-2-benzyl-4-oximino-3oxobicyclo[3.2.1 ]octane To a solution of 2-aza-2-benzyl-3-oxobicyclo[3.2.1]octane in THF was added 2.5 eq. of IM t-BuOK/THF (Aldrich) and the resulting mixture was stirred for 30 minutes. Isoamyl nitrite (1.5 eq.) was then added dropwise and the reaction mixture was stirred overnight. To the reaction mixture was added 3N HCI and this mixture was extracted with ethyl acetate and the organic extracts washed with water, dried, and concentrated under reduced pressure.
The residue was triturated with ether/hexanes, the solvents decanted and the residue dried under reduced pressure to afford 2-aza-2-benzyl-4-oximino-3oxobicyclo[3.2.1]octane as a tan liquid (41% yield). This procedure is further described in Y. Kim, Tetrahedron Lett. 30(21), 2833-2636 (1989).
Step D: Synthesis of 2-Aza-2-benzyl-4-amino-3oxobicyclo[3.2.1 ]octane A solution of 2-aza-2-benzyl-4-oximino-3-oxobicyclo[3.2.1]octane in mL/mmole of ethanol and 5.8 mL/mmole of 3N HCI containing 0.5 g/mmole of Pd/C was saturated with hydrogen gas to 45 psi. The mixture was shaken for 3 hours and then filtered through a layer of Celite. The filtrate was dried over sodium sulfate and concentrated under reduced pressure to afford the title compound as a solid (86% yield). This procedure is further described in E.
Reimann, Arch. Pharm. 310, 102-109 (1977).
Example 5-1 Synthesis of 3-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-y-butyrolactam Following General Procedure E above using alanine (Example B) and 3-amino-y-butyrolactam (prepared by the procedure of WO 98/28268 PCT/US97/22986 258-- S. Wilkinson, J1. Chem. Soc. 1951, 104), the title compound was prepared as a solid having a melting point of 21 7-222'C. The reaction was monitored by tic on silica gel (Rf 0. 19 in 1:9 methanol/dichloromethane).
NMR data was as follows: 'H-nmnr (DMSO-d 6 8 1.20 (in, 3H), 1.75 (in, 1H), 2.27 (in, 1H), 3.15 (in, 2H1), 3.51 111), 3.52 111), 4.28 (in, 211), 6.99 (in, 211), 7.09 (mn, 1H), 7.85 (mn, 1H1), 8.19 (in, 111), 8.34 J 7.8 Hz, 1H).
3 C-nrnr (DMSO-d 6 18.7, 28.4, 28.5, 37.98, 38.00, 41.3, 41.5, 48.07, 48.11, 49.4, 49.5, 101.9 J 25.3 Hz), 112.2 140.8, 162.1 (dd, J 13.5, 243.6 Hz), 168.6, .168.7, 172.27, 172.29, 174.2, 174.3.
C
15
H
17
N
3 0 3
F
2 (MW 325.32); mass spectroscopy 326.
Example 5-2 Synthesis of 3-(N 6-valerolactamn Following General Procedure A and using N-(3 alanine (Example B) and 3-amino-8-valerolactam (prepared by the procedure of D. W. Adamson, J1 Chern. Soc. 1943, 39), the title compound was prepared.
Example 5-3 Synthesis of 1-Benzyl-3-(S)-(N '-(3,S-difluorophenylacetyl)-L-alaninyl)amino-6-valerolactam Following General Procedure A above using alanine (Example B) and 3-(S)-ainino- 1-benzyl-5-valerolactam (Example the title compound was prepared as a solid having a melting point of 172-1 The reaction was monitored by tic on silica gel (Rf 0.39 in methanol/dichioromethane) and purification was by silica gel chromatography.
NMR data was as follows: 'H-nmr (CDCl 3 6 7.5 (in, 1H1); 7.37 Kd J=7.7, 1H1); 7.3 (in, 5H); 6.80 J 2H); 6.65 J 8.9, 1 4.7 (in, 2H1); 4.6 1H); 4.3 (in, 1H1); 3.50 211); 3.2 (in, 2H); 1.9 (in, 411); 1.3 (in, 311).
WO 98/28268 PCT1US97122986 -259 3 C-nr (CDCl 3 5 173.2, 170.3, 169.8, 165.2, 161.9, 139.4, 137. 1, 129.3, 128.4, 113.0, 112.8, 103.4, 102.0, 51.5, 51.3, 49.5, 47.1, 43.2, 27.7, 21.5, 19.4.
C
2 3 H25F 2
N
3
O
3 (MW 429); mass spectroscopy 430.
Example 5-4 Synthesis of 3-(N 4-methyl-e-caprolactam Following General Procedure B above using alanine (Example B) and 3-amino-4-methyl-s-caprolactam (General Procedure the title compound was prepared as a mixture of diasteromers. The reaction was monitored by tic on silica gel (Rf =0.18 in 5% MeOHldichloromethan).
NMR data was as follows: 'H-nmr (DMSO-d 6 2 diasteromers): 8 8.36 (in, IH), 7.78 (in, 2H), 7.06 (114), 6.96 (mn, 2H), 4.32 (in, 2H), 3.50 2H), 3.14 (in, IH), 3.04 (mn, 1H), 1.80 (in, 1H), 1.70 (in, IH), 1.08-1.55 (in, 1.20 J 7.1 Hz, 3H), 0.80 (in, 3H).
1 3 C-nmr (DMSO-d 6 2 diasteromers): 8 174.1, 174.0, 171.9, 171.8, 169.1, 168.9, 162.4 (dd, J 13.6, 246.0 Hz), 140.9 J 10. 1 Hz), 112.4 (dd, J 2.4, 24.2 Hz) 102.0, J 26.0 Hz), 54.2, 54.0, 48.5 (overlapping), 41.4, 36.7, 36.4, 34.5, 34.3, 28.2, 28.0, 18.9, 18.8, 18.6, 18.0.
C,
8
H.,
3
N
3 0 3
F
2 (MW 367.40); mass spectroscopy (M+Na) 390.5.
Example Synthesis of 3-(N 1 ,2,3,4-tetrahydroq uinolin-2-one Following General Procedure A above using alanine (Example B) and 3 -amino- 1,2,3,4-tetrahydroquinolin-2-one (Example the title compound was prepared as a mixture of diasteroiners. The reactio 'n was monitored by tlc on silica gel (Rf 0.38 in 25% ethyl acetate/hexanes) and WO 98/28268 PCT/US97/22986 260 purification was by flash chromatography using 25% ethyl acetate/hexanes as the eluant.
NMR data was as follows: 'H-nmr (DMSO-d 6 2 diasteromers): 6 10.34 1H), 8.41 1H), 8.23 1H), 7.20 6.86 7H), 4.40 2H), 3.52 2H), 3.52 2H), 3.05 2.79 2H), 1.29 1.5H), 1.24 "C-nmr (DMSO-d 6 2 diasteromers): 5 172.66, 169.31, 169.21, 169.13, 168.89, 137.85, 128.58, 126.46, 127.94, 122.88, 122.79, 122.69, 122.64, 115.48, 112.97, 112.88, 112.73. 112.59, 112.51, 102.24, 48.61, 48.17, 41.68, 31.72, 18.96, 18.87.
C
2 0
HI
9
N
3 0 3
F
2 (MW 387.39).
Example 5-6 Synthesis of 1-Benzyl-3-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino- 1,2,3,4-tetrahydroquinolin-2-one Following General Procedure C above using alanine (Example B) and 3-amino-l-benzyl-l,2,3,4-tetrahydroquinolin-2-one (General Procedure the title compound was prepared as a solid having a melting point of 196-199 0 C. The reaction was monitored by tic on silica gel (Rf 0.35 in 5% methanol/dichloromethane) and purification was by flash chromatography using 5% methanol/dichloromethane as the eluant.
NMR data was as follows: 'H-nmr (CDC1 3 6 7.4-6.8 12H), 6.7 1H), 6.45 1H), 5.4 1H), 4.9 1H), 4.6 2H), 3.55 2H), 3.45-3.40 (2xd, 1H), 2.85 (t, 1H), 1.45 3H).
3 C-nmr (CDC1 3 6 172.7, 172.6, 169.9, 169.7, 169.2, 169.2, 165.4, 165.2, 162.1, 161.9, 139.3, 138.7, 138.6, 136.8, 129.4, 129.3, 128.7, 128.0, 126.9, 124.8, 124.8, 124.6, 124.5, 116.5, 113.1, 113.05, 113.0, 112.9, 112.86, 112.8, 112.8, 112.7, 103.8, 103.5, 103.1, 50.1, 49.7, 49.6, 48.0, 47.9, 43.5, 32.3, 32.12, 32.1, 19.4, 19.2.
C
2 7
H
25
N
3 0 3
F
2 (MW 477.51); mass spectroscopy (MH 478.
WO 98/28268 WO 9828268PCIUS97/22986 261 Example 5-7 Synthesis of 4-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)ainino- 1 ,2,3,4-tetrahydroisoquinolin-3-one Following General Procedure D above using L-alanine and 4-amino- 1, 2,3 ,4-tetrahydroisoquinoline-3 -one, the title compound was prepared as a solid having a melting point of 243-244*C.
NMR data was as follows: 'H-nr (DMSO-d 6 8 8.46 (bt, J 8.25 Hz, 2H), 8.36-8.38 (bd, J 4 Hz, IH), 7.3-7.0 (in, 7H), 5.34-5.39 (bd, J 10 Hz, 1H), 4.5-4.4 (in, 2H), 4.2- 4.23 (in, lH), 3.56 2H1), 1.33 J 7 Hz, 3H).
C
20
H-
19
N
3 0 3 F7, (MW 387.1); mass spectroscopy: 387.
Example 5-8 Synthesis of 4-(N '-(3,5-Difluorophenylacetyl)-L-alaninyl)ainino-2-benzyl- 1 ,2,3,4-tetrahydroisoquinolin-3-one Following General Procedure D above using alanine (Example B) and 4-amino-2-benzyl- 1 ,2,3,4-tetrahydroisoquinoline-3 -one (General Procedure the title compound was prepared as a solid having a melting point of 144-145'C.
NMR data was as follows: 'H-nr (DMSO-d 6 5 7.8 (bd, 0.5H), 7.57 (bd, 0.5H), 7.26-7.0 (in, 9H), 6.8-6.6 (mn, 6.66-6.3 (in, 1H), 5.5-5.43 (in, 111), 4.79-4.45 (in, 5H), 4.10 (t, J 14 Hz, 1H), 3.49 2H), 5.52 J 7.0 Hz, 1.514), 1.49 J =7.0 Hz, 5
N
3 0 3 F. (MW 477); mass spectroscopy: 477.
Example 5-9 Synthesis of 4-(N '-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1-methyl- 1 ,2,3,4-tetrahydroisoquinolin-3-one WO 98/28268 PCT/US97/22986 262 Following General Procedure D above using N-(3 L-alanine (Example B) and 4-amino-i-methyl-i ,2,3,4-tetrahydroisoquinoline-3one (General Procedure the title compound was prepared as a solid having a melting point of 205-206 0
C.
NMR data was as follows: 'H-nmr (DMSO-d 6 6 8.6-8.24 (in, 3H), 7.3-7.0 (in, 7H aromatic), 5.4- 5.39 (mn, 1H), 4.58-4.4 (in, 2H), 3.54 2H), 1.49-1.38 (in, 1H), 1.35-1.3 (in.
6H).
C,,H,,N
3 0 3
F
2 (MW 401); mass spectroscopy: 401.
Example 5-10 Synthesis of 4-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-l-phenyl- 1,2,3,4-tetrahydroisoquinolin-3-one Following General Procedure D above using L-alanine (Example B) and 4-amino-i -phenyl- 1,2,3 ,4-tetrahydroisoquinoline-3one (General Procedure the title compound was prepared as a solid having a melting point of 200-205 0
C.
NMR data was as follows: IH-rnr (DMSO-d 6 86 9.06 (bt, J 2 Hz, 1H), 8.69-8.43 (in, 2Hz), 7.55- (mn, 2H), 6.1 (bd, J 8 Hz, 0.25H), 5.7-5.5 (in, lH), 5.5 (bd, J 8 Hz, 0.25H), 5.2-5.19 (bd, J 8 Hz, 0.5H), 4.48-4.4 (in, 1H), 3.57-3.5 (in, 2H), 3.15 1H), 1.4-1.2 (in, 3H).
C,-
6
H
23
N
3 0 3
F
2 (MW 463); mass spectroscopy: 463.2.
By employing the above procedure using trans-4-amino-1-phenyl-1 ,2,3,4tetrahydroisoquinoline-3-one and purifying the resulting product by LC 2000 chromatography, eluting with dichloromethane/methanol the following isomers of trans-4-(N' 5-difluorophenylacetyl)-L-alaninyl)amino-l1-phenyl- 1, 2,3 ,4-tetrahydroisoquinolin-3 -one were prepared: Isomer 1: m.p. 249-250'C.
Isomer 2: m.p. 232-233*C.
WO 98/28268 PCT/US97/22986 263 By employing the above procedure using cis-4 -amino- 1-phenyl- 1,2,3,4tetrahydroisoquinoline-3-one and purifying the resulting product by LC 2000 chromatography, eluting with dichioromethane/methanol the following isomers of cis-4-(N ,5-difluorophenylacetyl)-L-'alaninyl)amino- 1-phenyl- 1,2,3 ,4-tetrahydroisoquinolin-3-one were prepared: Isomer 1: m.p. 244.1-244.5*C.
Isomer 2: m.p. 247-248*C.
Example 5-11 Synthesis of -(3,5-Difluorophenylacetyl)-L-alaninyl)amino-6-fluoro- 1 ,2,3,4-tetrahydroisoquinolin-3-one Following General Procedure D above using N-(3 L-alanine (Example B) and 4-anxino-6-fluoro- 1,2,3 ,4-tetrahydroisoquinoline-3one (General Procedure the title compound was prepared as a solid having a melting point of 195-200*C.
NMR data was as follows: 'H-nmr (DMSO-d 6 8 8.6-8.41 (in, 3H), 7.4-7.24 (in, 1H), 7.09-6.98 (mn, 4H), 6.8-6.77 (bd, J =9 Hz, 111), 5.43-5.30 (mn, 1H), 4.46-4.42 (mn, 2H), 4.23- 4.19 (in, lH), 3.34 2H), 1.37 1.31 (in, 3H).
C
1 9
H-
18
N
3 0 3 F, (MW 405.3); mass spectroscopy: 405.
Example 5-12 Synthesis of 4-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-7-fluoro- 1 ,2,3,4-tetrahydroisoquinolin-3-one Following General Procedure D above using N-(3 L-alanine (Example B) and 4-amino-7-fluoro-1 ,2,3,4-tetrahydroisoquinoline-3one (Example the title compound was prepared. The product was purified by slurrying in ether/hexanes 1) and by LC 2000 chromatography, eluting with methanol/ethyl acetate to give the product as a solid (Isomer 1: m.p. 230-235*C; Isomer 2: in.p. 195-200*C).
NMR data was as follows: WO 98/28268 PCTUSM722986 264 'H-nmr (DMSO-d 6 8 7.25-6.9 (in, 6H), 5.4 J =8 Hz, IH), 4.6-4.4 (in, 2H1), 3.55 2H), 1.35 J 7.5 Hz, 1.5H), 1.32 J 7.2 Hz,
C,
0
H,
8
N
3 0 3
F
3 (MW 405); mass spectroscopy: 405.
Example 5-13 Synthesis of 4-(N '-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-2-phenethyl- 1,2,3,4-tetrahydroisoquinolin-3-one Following General Procedure D above using alanine (Example B) and 4-amino-2-phenethyl- 1,2,3 ,4-tetrahydroisoquinoline-3one (General Procedure the title compound was prepared as a solid having a melting point of 75-76 0
C.
C,.H,
7
N
3
O
3 F, (MW 491); mass spectroscopy: 491.2.
Example 5-14 Synthesis of 4-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-3-one Following General Procedure D above using L-alanine (Example B) and 4-amino-2-methyl- 1,2,3 ,4-tetrahydroisoquinoline-3one (General Procedure the title compound was prepared as a solid having a melting point of 174-175 0
C.
NMR data was as follows: 'H-nmr (DMSO-d 6 6 8.57-8,47 8.45 J 7.6 Hz, lH), 7.26- 7.06 (in, 7H aromatic), 5.38 J 8.3 Hz, 111), 4.68 J 16 Hz, IH), 4.41 (pentet, J 8 Hz, IH), 4.42 J 16 Hz, 1H), 3.5 211), 2.9 3H), 1.34 J 8 Hz, 1.5 Hz), 1.32 J 8 Hz,
C,
1
H,
1
N
3 0 3 F, (MW 401); mass spectroscopy: 401.
Example 5-15 Synthesis of 4 -(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-6-phenyl- 1 ,2,3,4-tetrahydroisoquinolin-3-one WO 98/28268 PCTIUS97/22986 265 Following General Procedure D above using L-alanine (Example B) and 4-amino-6-phenyl- 1,2,3 ,4-tetrahydroisoquinoline-3one (General Procedure the title compound was prepared. The product was purified by LC 2000 chromatography, eluting with ethyl acetate.
NMR data was as follows: 'H-nmr (CD 3 OD/CDCl 3 6 8.8 (bd, 0.5H), 7.74 (bd, 7.4-7.16 (in, 6H), 6.69 (bs, 6.69 (bs, IH), 6.5 (in, 1H), 5.39 (bs, lH), 4.45-3.95 (in, 4H), 1.37-1.33 (in, 3H).
C
26
H
23
N
3 0 3
F
2 (MW 463.49); mass spectroscopy: 463.4.
Example 5-16 Synthesis of 4-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-7-phenyl- 1 ,2,3,4-tetrahydroisoquinolin-3-one Following General Procedure D above using L-alanine (Example B) and 4-amino-7-phenyl- 1,2,3 ,4-tetrahydroisoquinoline-3one (Example the title compound was prepared as a solid having a melting point 240*C (dec.).
NMR data was as follows: 'H-nmr (CDCl 3 6 7.5-7.18 (in, 101-), 6.85-6.74 (in, 4H), 4.9-4.57 (in, 4.56-4.37*(in, 2H), 3.508 3.55 1H), 1.53 J =6 Hz, 1.51-), 1.47 J 6 Hz, C,1 6
H
23
N
3 0 3
F
2 (MW 463); mass spectroscopy: 463.
Example 5-17 Synthesis of (N '-(3,5-DiE Iuorophenylacetyl)-L-alaninyl)- (9-aminofluroren-1-yl)glycine 6-Lactam Following General Procedure D above using L-alanine (Example B) and (9-aminofluroren- 1-yl)glycine c-lactam (General Procedure the title compound was prepared as a solid having a melting point 240*C (dec.).
NMR data was as follows: WO 98/28268 PCTUS97/22986 266 'H-nmr (DMSO-d 6 8 8.0-6.8 (bin, IOR), 6.3-5.75 (bs, 1H), 5.75-5.4 (bs, 111), 4.1-4.5 (bs, IH), 3.7-3.35 (bin, 2H), 3.3 2H), 1.4-1.0 (bin, 3H).
C
26
H,)N
3 0 3
F
2 (MW 461); mass spectroscopy: 461.
Example 5-18 Synthesis of 3-(N '-(Phenylacetyl)-L-alaninyl)amino-E-caprolactam Following General Procedure B above using N-(phenylacetyl)-L-alanine (Example A) and 3-amino-E--caprolactam (Sigma), the title compound was prepared as a solid having a melting point of 200-202*C. The reaction was monitored by tlc on silica gel (Rf 0.30 in 1:9 methanol/dichloromethane).
NMR data was as follows: 'H-nmr (DMSO-d 6 6 8.35 (in, 1H), 7.85 (in, 2H), 7.28-7.32 (in, 4.22-4.40 (in, 2H), 3.46 2H), 2.98-3.13 (in, 2H), 1.53-1.90 (in, 4H), 1.26- 1.40 (in, 1H), 1.20 (in, 4H).
1 3 C-nmr (DMSO-d 6 6 174.05, 174.02, 171.2, 171.1, 169.9, 169.8, 136.31, 131.29, 129.1, 129.0, 128.2, 126.3, 51.3, 48.3, 42.0, 40.6, 31.2, 31.0, 28.8, 27.6, 18.2, 18.1.
C
17
H
23
N
3 0 3 (MW =317.39) mass spectroscopy (MW) 316.
Example 5-19 Synthesis of Samino-e-caprolactam Following General Procedure B above using alanine (Example B) and 3-(S)-amino-F-caprolactam (Aldrich), the title compound was prepared as a solid having a melting point >225C. The reaction was monitored by tlc on silica gel (Rf 0.36 in 1:9 methanol/dichloromethane).
NMR data was as follows: 'H-ninr (DMSO-d 6 6 1.10-1.40 (in, 2H), 1.21 J 7.1 Hz, 3H), 1.55-1.90 (in, 4H), 3.05 (in, 1H), 3.17 (in, 1H), 3.52 2H), 4.29 (in, 2H), 6.98 (mn, 2H), 7.08 (in, 1H), 7.84 (in, 2H), 8.43 J 7.3 Hz, 1H).
WO 98/28268 PCT/US97/22986 267 3 C-nmr (DMSO-d 6 6 18.0, 27.6, 28.8, 31.0, 40.6, 41.3, 48 51.3, 101.9 J 25.6 Hz), 112.3 (dd, J 7.5, 16.8 Hz), 140.6, 162.1 (dd, J 13.2, 243.9 Hz), 168.8, 171.1, 174.0.
C
17
H
21
N
3 0 3
F
2 (MW =353.37 mass spectroscopy 354.
Example 5-20 Synthesis of 3-(S)-(N'-(3,5-difluorophenylacetyl)-L-alaninyl)amino- 1-benzyl-e-caprolactamn Following General Procedure B above using L-alanine (Example B) and 3-(S)-amino-1-benzyl-c--caprolactam (prepared from 3-(S)-amino-E--caprolactam and benzyl bromide using the procedure of Example 6-A and General Procedure the title compound was prepared as a solid having a melting point of 176-178 0 C. The reaction was monitored by tic on silica gel (Rf 0.44 in 10% methanol/dichioromethane) and purification was by precipitation from water.
NMR data was as follows: 'H-nmr (CDC1 3 6 1.20 (in, 1H), 1.39 J 7.0 Hz, 3H), 1.50 m, 1H), 1.65-2.06 (in, 4H), 3.24 (mn, 1H), 3.45 (in, 1H), 3.54 2H), 4.51 (in, 2H), 4.60 (in, 1H), 4.72 14.5 Hz, 1H), 6.48 J 7.1 Hz, 1H), 6.72 (in, 1H), 6.83 (mn, 2H), 7.20-7.41 (in, 6H).
13 C-nmr (CDCl 3 6 19.0, 26.9, 27.5, 31.7, 42.8, 48.0, 49.0, 51.5, 52.4, 102.6 J 25.2 Hz), 112.2 (dd, J 8.0, 17.0 Hz), 127.6, 128.1, 128.7, 136.7, 138.4, 162.9 (dd, J =12.8, 247.3 Hz), 169.0, 171.0, 172.5.
C
24
H
27
N
3 0 3
F
2 (MW 443.50) mass spectroscopy 444.
Example 5-21 Synthesis of 3-(S)-N'-(3,5-Difluorophenylacetyl)-L-alaninyl)aminol-(2-Methoxyethyl)-E.-caprolactam Following General Procedure B above using -difluorophenylacety l)-L alanine (Example B) and 3 -(S)-ainino-1-(2-inethoxyethyl)-6-caprolactam (prepared from 3-(S)-amino-F,-caprolactam and 2-methoxyethyl bromide using WO 98/28268 PCTIUS97/22986 268 the procedure of Example 6-A and General Procedure 6-B3), the title compound was prepared as a solid having a melting point of 102-1 06*C. The reaction was monitored by tic on silica gel (Rf =0.08 in 5% methanol/dichloromethane).
NMR data was as follows: 'H-nnir (CDC1 3 6 1.38 J 7.1 Hz, 3H), 1.48 (in, 2H), 1.82 (in, 2H), 1.96 (in, 2H), 3.35 3H), 3.38 (in, 1H), 3.47-3.70 (in, 7H), 4.55 (in, 2H), 6.75 (in, 2H), 6.85 (mn, 2H), 7.42 J 6.0 Hz, 1H).
1 3 C-ninr (CDCl 3 6 19.0, 27.1, 27.6, 31.7, 42.8, 48.7, 49.0, 49.9, 52.4, 58.8, 70.9, 102.6 J =25.2 Hz), 112.2 (dd, J 7.8, 16.9 Hz), 138.4, (164.5, 161.4, 161.2 as multiplet), 169.0, 171.0, 172.4.
C
20
H
27
N
3 0 4
F
2 (MW 411.45); mass spectroscopy 412.
Example 5-22 Synthesis of 3-(S)-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino- 1 -ethyl-E-caprolactam Following General Procedure B above using alanine (Example B) and 3-(S)-amino-lI-ethyl -&-caprolactarn (prepared from 3- (S)-amino-s-caprolactam and ethyl iodide using the procedure of Example 6-A and General Procedure the title compound was prepared as a solid having a melting point of 162-165'C. The reaction was monitored by tlc on silica gel (RI 0.43 in 10% methanol/dichloroinethane).
NMR data was as follows: 'H-ninr (CDC1 3 6 1.12 J 7.1 Hz, 3H), 1.40 (mn, 2H), 1.36 J =7.0 Hz, 3H), 1.70-2.00 (mn, 4H), 3.24 (in, 1H), 3.50 (in, 3H), 3.53 2H), 4.50 (in, 2H), 6.70 (mn, 2H), 6.83 (in, 2H), 7.39 J 6.0 Hz, 1H).
1 3 C-nmr (CDCl 3 8 13.1, 19.1, 27.6, 27.7, 31.7, 42.8, 43.5, 48.1, 49.0, 52.3, 102.6 J 25.1 Hz), 112.2 (dd, J 7.9, 17.0 Hz), 138.3, 138.4, 163.0 (dd, J 12.8, 247.1 Hz), 168.9, 170.9, 171.8.
C
19
H
25
N
3 0 3
F
2 (MW 381.43); mass spectroscopy 382.
WO 98/28268 PCTIUS97/22986 269 Example 5-23 Synthesis of 3-N Following- General Procedure B above using alanine (Example B) and 3-amino-5-ethyl-c-caprolactam (General Procedure the title compound was prepared as a solid. The reaction was monitored by tlc on silica gel (Rf 0.13 in 5% methanol/dichioromethane).
NMR data was as follows: 'H-nmr (CDCl 3 8 0.98 J 7.4 Hz, 3H), 1.31 J 7.0 Hz, 1.35 J 7.1 Hz, 1.5H), 1.55 (in, 1H), 1.65 (in, 3H), 1.82 (in, 2H), 1.95 (in, 1H), 3.06 (in, 1H), 3.41 (in, 1H), 3.49 1H), 3.52 111), 4.55-4.72 (in, 2H), 6.38 (mn, 0.5H), 6.63-6.90 (in, 4.5H), 7.37 J Hz, 0.5H), 7.52 J 6.2 Hz, 3 C-nmr (CDCl 3 8 12.07, 12.11, 19.0, 19.2, 24.4, 24.5, 31.9, 32.0, 35.0, 35.3, 35.7, 36.9, 37.0, 42.8, 47.4, 47.6, 48.8, 48.9, 102.7 102.6 122.2 (multiplet of 138.35, 138.41, 138.5, 163.0 (dd, J 12.8, 247.1 Hz), 168.9, 169.2, 171.1, 171.3, 174.8, 174.9.
C
19
H
25
N
3 0 3
F
2 (MW =381.43); mass spectroscopy 382.
Example 5-24 Synthesis of 3-N Following General Procedure B above using alanine (Example B) and 3-aniino-5-ethyl-Es-caprolactam (General Procedure the title compound was prepared as a solid having a melting point of 201 204'C (decom.). The reaction was monitored by tlc on silica gel (Rf =0.04 in methanol/dichloroinethane).
NMR data was as follows: 'H-nmr (CD 3 OD): 6 0.70 J 7.1 Hz, 311), 0.78-1.20 (in, 7H), 1.49 (in, 1H), 1.68 (mn, 2H1), 3.07 (in, 2H), 3.38 2H1), 4.19 (in, 1H1), 4.31 J 11.0 Hz, 1H1), 6.61 (in, 1H), 6.72 (in, 2H).
WO 98/28268 WO 98/8268 TIUS97/22986 270 3 Cnr (CD 3 OD): 6 11.47, 11.49, 17.8, 17.9, 31.0, 35.97, 36.03, 38.2, 38.3, 41.6, 42.7 (multiplet of 50.7, 50.8, 52.3, 103.0 (2 triplets of 113.2 (2 dd of 140.9, 141.0, 164.3 (dd, J 15.5, 258.3 Hz), 172.5 (overlapping of 173.7, 173.9, 176.5, 176.6.
C
19
H
25
N
3 0 3
F
2 (MW 381.43); mass spectroscopy 382.
Example 5-25 Synthesis of 3-(N 7-benzyl-c--caprolactam Following General Procedure B above using alanine (Example B) and 3-amino-7-benzyl-e-caprolactam (General Procedure the title compound was prepared as an oil. The reaction was monitored by tic on silica gel (Rf =0.04 in 5% methanol/dichloromethane).
NMR data was as follows: 'H-nmr (CDCl 3 8 1.35 (in, 3H), 1.45 (in, 111), 1.80 (in, 2H), 2.05 (d, J 7.2 Hz, 2H), 2.10 (mn, 1H), 2.97 (in, 2H), 3.51 and 3.52 (2 s, 3H), 4.60 (in, 2H), 6.50 6.85 (mn, 5H), 7.15 (in, 2H), 7.26 (in, 3H1), 7.45 (in, 1H).
1 3 C-nmr (CDCl 3 8 18.7, 20.0, 21.6, 30.2, 30.4, 30.7, 39.1, 39.3, 42.5, 48.70, 48.74, 53.02, 53.06, 53.89, 53.97, 102.5 J 25.4 Hz), 112.2 (dd, J 8.3, 17.2 Hz), 126.68, 126.74, 128.67, 128.71, 128.9, 138.0, 138.1, 138.6, 138.7, 138.8, 163.0 (dd, J 13.0, 249.0 Hz), 169.5, 169.6, 172.0, 174.4, 175.0.
C
24
H
27
N
3 0 3
F
2 (MW =443.50).
Example 5-26 Synthesis of 1 -benzyl-4,7-methano-E--caprolactam Following General Procedure A above using alanine (Example B) and 3-(S)-ainino-l1-benzyl-4,7-methano-s-caprolactain 4-ainino-2-aza-2-benzyl-3-oxobicyclo[3.2. 1 j octane hydrochloride from Example the title compound was prepared as an oil. The reaction was monitored by WO 98t28268 PCTIUS97/22986 271 tic on. silica gel (Rf 0.42 in 10% methanol/dichioromethane) and purification was by silica gel chromatography.
N MR data was as follows: 'H-nmr (CDCl 3 6 7.3 (in, 5H); 6.82 J=6.3, 6.0, 2H); 6.6 (in, 111); 5.14 (dd, J 8.5, 6.4, 1 4.6 (in, 2H); 3.79( dd, J =10. 3, 4.5, 10.4, 1H). 3.56 1H); 3.51 211); 2.8 (in, 1H); 2.57 1110; 1.96 J=12.1, 1H); 1.7 (in, 4H); 1.34 J=7.0, 3H).
3 C-nmr (CDCl 3 8 173.4, 170.3, 168.9, 165.2, 139.4, 137.3, 129.3, 128.5, 128.2, 112.9, 112.8, 112.7, 112.6, 103.4, 103.0, 102.7, 59.0, 49.6, 43.1, 38.1, 37.8, 36.6, 32.6, 22.7, 19.2.
C
25
H
27
F
2
N
3 0 3 (MW 455); mass spectroscopy 456.
Example 5-27 Synthesis of '-(Cyclopentylacetyl)-L-alaninyl)amino- 1-benzyl-ce-caprolactamn Following General Procedure A above using N-(cyclopentylacetyl)-L-alanine (Example D) and -amino-1I-benzyl-E-caprolactan (prepared from amino-F-caprolactamn and benzyl bromide using the procedure of Example 6-A and General Procedure the title compound was prepared. The reaction was monitored by tic on silica gel (Rf 0.37 in 5% methanol/dichloroinethane) and purification was by preparative thin layer chromatography using methanolldichloromethane as the eluant.
NMR data was as follows: 'H-nmr (CDCl 3 6 7.42 J=6.0 Hz, 1H), 7.15-7.05 (in, 5H1), 6.36 (d, 7.2 Hz, IH), 4.8-4.4 (in, 4H), 3.5-3.3 (in, 1H), 3.3-3.1 (mn, 11H), 2.3-1.0 (in, 20H1).
3 C-nmr (CDCl 3 6 172.8, 172.4, 171.5, 136.9, 128.7, 128.2, 127.7, 52.3, 51.4, 48.6, 47.9, 47.6, 42.6, 36.9, 32.34, 32.28, 31.6, 27.5, 26.8, 24.8, 19.0, 18.4.
C,
3
H
3 3
N
3 0 3 (MW =.399.54); mass spectroscopy (M+Na) 422.
WO 98/28268 PCTIUS97I22986 272 Example 5-28 Synthesis of '-(Cyclopentylacetyl)-L-phenylglycinyl)amino- 1-benzyl-e-caprolactam Following General Procedure A above N-(cyclopentylacetyl)-L-2phenylglycine (Example C) and 3-(S)-amino- I-benzyl-6-caprolactam (prepared from 3-(S)-amino-F,-caprolactam and benzyl bromide using the procedure of Example 6-A and General Procedure the title compound was prepared.
The reaction was monitored by tic on silica gel (Rf =0.40 in methanol/dichioromethane) and purification was by preparative thin layer chromatography using 5% methanol/dichloromethane as the eluant.
NMR data was as follows: 'H-nmr (CDCl 3 8 7.4-7.15 (in, lIR), 6.79 J=6.6 Hz, IRH), 5.48 (d, J=7.2 Hz, lH), 4.5 (mn, 3H), 3.4-3.1 (in, 2H), 2.3-1.0 (in, 17H).
3 C-nmr (CDCl 3 5 172.3, 172.1, 168.9, 138.0, 129.0, 128.6, 128.2, 128.1, 127.6, 127.0, 57.1, 52.6, 51.3, 47.8, 42.5, 36.8, 32.33, 32.27, 31.4, 27.4, 26.8, 24.7.
C,1 3
H
33
N
3 0 3 (MW 461.61); mass spectroscopy (M+Na) 484.
Example 5-29 Synthesis of 1-(2-phenethyl)-e-caprolactam Following General Procedure A above using alanine (Example B) and 3-(S)-amino-1-(2-phenethyl)-c-caprolactam (prepared from 3-(S)-amino-F,-caprolactam and 2-phenethyl bromide using the procedure of Example 6-A and General Procedure 6-B3), the title compound was prepared.
The reaction was monitored by tlc on silica gel (Rf 0.36 in methanol/dichioromethane) and purification was by preparative thin layer chromatography using 5% inethanol/dichloromethane as the eluant.
NMR data was as follows: 'H-ninr (CDCl 3 5 7.60 J=6.3 Hz, lH), 7.3-7.1 (in, 6H), 6.81 (in, 2H), 6.66 (mn, 1H), 4.6 (in, 2H), 3.75 (in, 1H), 3.51 2H1), 3.5-3.4 (in, 2H), WO 98/28268 PCT/US97/22986 273 3.05 (in, 2.8 (in, 1.95-1.6 (mn, 4H1), 1.5-1.1 (m (includes d at 1.36, J=7.2 Hz, 3 C-nmr (CDCI 3 8 172.3, 171.5, 169.2, 164.6, 164.5, 161.4, 161.2, 139.0, 138.8, 138.7, 138.6, 128.6, 128.5, 126.4, 112.3, 112.2, 112.05, 111.95, 102.7, 102.3, 102.0, 52.2, 50.8, 49.2, 48.9, 42.4, 34.1, 31.5, 27.3, 27.1, 18.8.
C,
5 1-I, 9
FN
3 0 3 (MW 457.52); mass spectroscopy (M+Na) 480.
Example 5-30 Synthesis of 3-(S)-(N'-(Cyclopentylacetyl)-L-phenylglycinyl)amino- 1-(2-phenethyl)-e-caprolactam Following General Procedure A above using N-(cyclopentylacetyl)-Lphenyiglycine (Example C) and 3-(S)-amnino-1-(2-phenethyl)-c-caprolactam (prepared from 3-(S)-amino-c-caprolactamn and 2-phenethyl bromide using the procedure of Example 6-A and General Procedure 6-B3), the title compound was prepared. The reaction was monitored by tic on silica gel (RI 0.47 in methanol/dichloromethane) and purification was by preparative thin layer chromatography using 5% methanol/dichloromethane as the eluant.
NMR data was as follows: 'H-nmr (CDCl 3 5 7.4-7.1 (in, I1IH), 6.88 J=7.2 Hz, I 5.49 (d, J=7.2 Hz, 4.2 (in, 1H), 3.7-3.6 (in, 11H), 3.5-3.3 (mn, 3.1-3.0 (in, 11H), 2.9-2.7 (in, 2.3-1.0 (in, 17H).
3 C-nmr (CDCl 3 8 172.2, 171.0, 169.0, 138.6, 138.2, 129.0, 128.7, 128.6, 128.2, 127.0, 126.5, 57.0, 52.6, 50.8, 49.3, 44.4, 42.5, 36.9, 34.2, 32.4, 32.3, 31.4, 27.5, 27.2, 24.8.
C,
9
H
37
N
3 0 3 (MW 475.64); mass spectroscopy (M+Na) 498.
Example 5-31 Synthesis of 3-(N '-(3,4-Dichlorophenyl)-D,L-alaninyl)amino-re-caprolactam Following General Procedure A above using N-(3,4-dichlorophenyl)-D,Lalanine (Example Q) and 3-(S)-amino-s-caprolactam (Sigma), the title compound WO 98/28268 PCT/US97/22986 274 was prepared as a solid having a melting point of 199 0 C. The reaction was monitored by tic on silica gel (Rf 0.4 in 50% ethyl acetate/hexanes) and purification was by preparative thin layer chromatography using 50% ethyl acetate/hexanes as the eluant.
NMR data was as follows: 'H-nmr (DMSO-d 6 6 7.2(d, 1H); 6.7 6.4 (dd, 1H); 4.30 (bs, 1H); 4.1 2H); 2.9 2H); 1.7 6H); 1.3 3H).
3 C-nmr (DMSO-d 6 6 175; 171; 146.7; 133; 131; 121; 114.9; 112.6; 52.4; 28.3; 27.5; 19.5; 18.2; 18.1.
C
15 19
N
3 0 2 C1 2 (MW 344.24); mass spectroscopy (MH 345.
Example 5-32 Synthesis of 3-(S)-(N'-(cyclopropylacetyl)-L-phenylglycinyl)amino- 1-methyl--caprolactam Following General Procedure A above using N-(cyclopropylacetyl)-Lphenylglycine (Example F) and 3-(S)-amino-l-methyl-e-caprolactam (prepared from 3-(S)-amino-E-caprolactam and methyl iodide using the procedure of Example 6-A and General Procedure the title compound was prepared as a solid having a melting point >200 0 C. The reaction was monitored by tlc on silica gel (Rf 0.41 in 10% methanol/dichloromethane) and purification was by recrystallization from ethyl acetate and hexanes.
NMR data was as follows: 'H-nmr (CDCI1): 6 7.5-7.2 7H), 5.49 J 6.6 Hz, 1H), 4.46 1H), 3.50 1H), 3.10 1H), 2.97 3H), 2.1-1.7 4H), 1.5-1.3 2H), 1.0 1H), 0.6 2H), 0.2 2H).
"C-nmr (CDC1 3 6 172.1, 171.8, 168.9, 138.1, 129.0, 128.3, 127.0, 57.0, 52.4, 50.2, 41.1, 35.8, 31.3, 27.5, 26.4, 6.8, 4.4.
C
20 oH2N 3 0 3 (MW 357.46).
WO 98/28268 PTU9128 PCTIUS97/22986 275 Example 5-33 Synthesis of 3-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino- 8-octanelactam Following General Procedure B above using L-alanine (Example B) and 3-amino-8-octanelactam 2-oxo-1azacyclononane prepared as described in General Procedure the title compound was prepared as a solid having a melting point of >220*C.
NMR data was as follows: 'H-nmr (DMSO-d 6 86 1.00 1.85 (in, 12H), 2.73 (in, 1H), 3.33 (br s, 2H), 3.49 (br s, 2H), 4.07 (in, 1H), 4.28 (in, 1H), 6.95 (in, 2H), 7.06 (in, 1H), 7.75 7.90 (in, 2H), 8.30 J 7.2 Hz, 1H).
3 C-nmr (DMSO-d 6 8 18.2, 18.6, 21.1, 23.5, 27.9, 28.1, 32.3, 32.6, 41.3, 48.0, 48.1, 52.9, 53.0, 102.0 J 25.9 Hz), 112.4 J 24.1 Hz), 141.0 J 11.2 Hz), 162.3 )dd, J 13.5, 244.5 Hz), 168.9, 171.9, 173.1, 173.2.
C
19
H
2 5
N
3 0 3
F
2 (MW 381.43); mass spectroscopy 380.
Example 5-34 Synthesis of 4-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-7-benzyl- 1 ,2,3,4-tetrahydroisoquinolin-3-one Following General Procedure D above using N-(3 alanine (Example B) and 4-amino-7-benzyl- 1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure the title compound was prepared as a solid having a melting point of 159-1 66*C.
C,-
7
H,
5
N
3 0 3 F, (MW 477); mass spectroscopy: 477.
Example 5-35 Synthesis of 4-(N '-(3,5-Difluorophenylacetyl)-L-alaninyl)amino- 1-benzyl- 1 ,2,3,4-tetrahydroisoquinolin-3-one WO 98/28268 WO 9828268PCT/US97/22986 276 Following General Procedure D above using alanine (Example B) and 4-amnino- I -benzyl- 1,2,3 ,4-tetrahydroisoquinoline-3 -one (Example the title compound was prepared as a solid having a melting point of 106-107TC.
C 7
H,
5
N
3 0 3 F, (MW 477.52); mass spectroscopy: 478.
Example 5-36 Synthesis of 4-(N '-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-2-methyl- 1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one Following General Procedure D above using alanine (Example B) and 4-amino-2-methyl- 1 -phenyl- 1,2,3,4tetrahydroisoquinoline-3 -one (General Procedure the title compound was prepared as a solid having a melting point of 115To.
C,_
7
H
24
N
3 0 3 F, (MW 476); mass spectroscopy: 477.
Example 5-37 Synthesis of 4-(N 1-(pyrid-2-yI)-1,2,3,4-tetrahydroisoquinolin-3-one Following General Procedure D above using alanine (Example B) and 4-amino-I -(pyrid-2-yl)-1I,2,3,4-tetrahydroisoquinoline- 3-one (Example the title compound was prepared as a solid having a melting point of 1 00TC.
C,
5
H
22
N
4 0 3
F
2 (MW 464); mass spectroscopy: 464.1.
Example 5-38 Synthesis of 4-(N 1-(pyrid-3-yI)-1 ,2,3,4-tetrahydroisoquinolin-3-one Following General Procedure D above using alanine (Example B) and 4-amino-i -(pyrid-3-yl)- 1,2,3 ,4-tetrahydroisoquinoline- WO 98/28268 PCTIUS97/22986 277 3-one (Example the title compound was prepared as a solid having a melting point of 100-1
C,
5
H,,N
4 0 3 F, (MW 464); mass spectroscopy: 464.
Example 5-39 Synthesis of 4-(N 1-(pyrid-4-yI)-1 ,2,3,4-tetrahydroisoquinolin-3-one Following General Procedure D above using alanine (Example B) and 4-amino-l-(pyrid-4-yl)-1 ,2,3,4-tetrahydroisoquinoline- 3-one (Example 5-13), the title compound was prepared as a solid having a melting point of 1 00 0
C.
C,sH,IN 4 0 3 F, (MW =464); mass spectroscopy: 464.
Example 5-40 Synthesis of 3-[N'-(3,5-Dit'Iuorophenylacetyl)-L-alaninyl]amino-1-methyl-2-indolinone Following General Procedure I above using N-(3 alanine (Example B) and 3 -amino- I -methyl-2-indolinone monohydrochioride (Example the title compound, as a 1: 1 diastereomeric mixture at C3 of the indolinone, was prepared as a white solid having a decomposition point of 215-220 0 C. Purification was by flash chromatography eluting with 3:1
CH
2 Cl 2 /EtOAc gradient to straight EtOAc followed by recrystalization from CHC1 3 Rf 0. 16 and 0. 22 (EtOAc).
C
20 HjqF 2
N
3 0 3 (MW 387.39); mass spectroscopy 387.0.
Anal. Calcd for C 20 HjqF 2
N
3 0 3 C, 62.01; H, 4.94; N, 10.85. Found: C, 61.76; H, 5.17; N, 10.65.
Example 5-41 Synthesis of 3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl] amino- 1-methyl-4-phenyl-3,4-trans-dihydrocarbostyriI WO 98/28268 PCT11JS97/22986 278 Following General Procedure I above using alamine (Example B) and the tin complex of 3 -amino- 1-methyl-4-phenyl-3,4trans-dihydrocarbostyril (Example 5 the title compound, as a 1: 1. 8 diastereomeric mixture of the two 3 ,4-trans-dihydrocarbostyril isomers, was prepared as a white solid (melting point 118-128 TC). Purification was by flash chromatography eluting with straight EtOAc. Rf 0.37 (EtOAc).
C
27 H25F 2
N
3 0 3 (MW 477.52); mass spectroscopy 477.
Anal. Calcd for C 27
H
25
F
2
N
3 0 3 C, 67.91; H, 5.28; N, 8.80. Found: C, 67.78; H, 5.35; N, 8.55.
Example 5-42 Synthesis of 3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]amino.
1-methyl-4-phenyl-3,4-cis-dihydrocarbostyriI Following General Procedure D above using L-alanine (Example B) and 3 -amino-i1 -methyl-4-phenyl-3 ,4-cisdihydrocarbostyril (Example the title compound was prepared as a white solid 152-153*C).
C
27 H25F 2
N
3
O
3 (MW 477.52); mass spectroscopy 478.2, (MH-) 476.2.
Anal. Calcd for C 27
H
25
F
2
N
3 0 3 C, 67.91; H, 5.28; N, 8.80. Found: C, 67.61; H, 5.41; N, 8.78.
Example 5-43 Synthesis of 3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyljamino- 4-phenyl-3,4-trans-dihydrocarbostyril Step A: Following General Procedure I above using difluorophenylacetyl)-L-alanine (Example B) and the tin complex of 3-amino-ltert-butoxycarbonyl-4-phenyl-3 ,4-trans-dihydrocarbostyriI (Example 3- ,5-difluorophenylacetyl)-L-alaninylI -amino- 1 -tert-butoxycarbonyl-4phenyl-3 ,4-trans-dihydrocarbostyril was prepared.
WO 98/28268 PCT/US97/22986 279 Step B: The title compound was prepared following General Procedure B using the product from Step A, as a 1:1.4 diastereomeric mixture of the two 3,4-trans-dihydrocarbostyril isomers. The product was purified by flash chromatography eluting with CH 2
CI
2 /MeOH (98:2 gradient to 94:6) and a second flash chromatography eluting with straight EtOAc to yield a white solid (melting point 137-147 Rf 0.42 (EtOAc).
C
2 6
H
23
F
2
N
3 0 3 (MW 463.49); mass spectroscopy 463.1 Anal. Calcd for C 26
H
23
F
2
N
3 0 3 C, 67.38; H, 5.00; N, 9.07. Found: C, 67.12; H, 5.06; N, 8.88.
6. Benzazepinone Derivatives and Related Compounds GENERAL PROCEDURE 6-A Alkylation of 1-Amino-1,3,4,5-tetrahvdro-2H-3-benzazepin-2-one Step A: 1-Ethoxycarbonylamino-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one was prepared according to the procedure of Ben-Ishai et al., Tetrahedron, 1987, 43, 430.
Step B: 1-Ethoxycarbonylamino-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one g, 100 was dissolved in DMF (30 mL) and NaH 0.17 g, 100M%) was added in one portion. The reaction mixture was stirred for 1 hour and then the appropriate alkyl iodide (300M%) was added and the mixture was stirred for 12 hours. The reaction was poured into water and extracted with ethyl acetate The ethyl acetate extracts were then washed with water (3x) and brine Treatment with MgSO 4 rotoevaporation, and chromotography EtOAc/hexanes) yielded 1-ethoxycarbonylamino-3-alkyl-1,3,4,5-tetrahydro- 2H-3-benzazepin-2-one in 87% yield.
Step C: 1-Ethoxycarbonylamino-3-alkyl-1,3,4,5-tetrahydro-2H-3benzazepin-2-one (1.0g, 100M%) was suspended in 30 mL of 30% HBr/HOAc WO 98/28268 WO 98268 PCT/US97/22986 280 and heated to 100 0 C. The reaction mixture was stirred for 5 hours at this temperature and then the reaction was cooled and rotoevaporated to yield 1amino-3-alkyl-l,3,4,5-tetrahydro-2H-3-benzazepin-2-one as the hydrobromide salt (100% yield).
GENERAL PROCEDURE 6-B Alkylation of 3-Amino- 1,3.4,5-tetrahydro-2H- 1 -benzazepin-2-one Step A: 3-Amino- 1,3,4,5-tetrahydro-2H- -benzazepin-2-one was prepared from ct-tetralone using the methods described in Armstrong et al. Tetrahedron Letters, 1994, 35, 3239. The following compounds were as prepared by this procedure for use in the following steps: 5-methyl-3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (from 4methyl-a-tetralone (Aldrich)); and 5,5-dimethyl-3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (from 4,4dimethyul-a-tetralone (Aldrich)).
Step B: 3-Amino-1,3,4,5-tetrahydro-2H-l-benzazepin-2-one (4.43 g, 100M%) was suspended in t-butanol (30mL) and BOC-anhydride (7.5 mL, 130M%) was added dropwise. The reaction was stirred for 2 hours and then it was rotoevaporated to a residue which was chromatographed with 60% ethyl acetate/hexanes to yield BOC-protected 3-amino-1,3,4,5-tetrahydro-2H-1benzazepin-2-one in 87% yield.
Step C: BOC-protected 3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one g, 100M%) was dissolved in DMF (20mL) and NaH 0.13g, 100M%) was added in one portion. The reaction mixture was stirred for 1 hour and then the appropriate alkyl iodide (300M%) was added and stirring was continued for 12 hours. The reaction was poured into water and extracted with ethyl acetate The ethyl acetate extracts were washed with water (3x) and then brine Treatment with MgSO 4 rotoevaporation, and chromotography WO 98/28268 WO 98/28268 PCT/US97/22986 281 EtOAc/hexanes) yielded a BOC-protected 3-amino-1-alkyl-1,3,4,5tetrahydro-2H-1-benzazepin-2-one in 80% yield.
Step D: The BOC-protected 3-amino-i-alkyl-1,3,4,5-tetrahydro-2H-1benzazepin-2-one (1.0g, 100M%) was suspended in 30 mL of 1:1
CH
2 Cl 2 /triflouroacetic acid and the mixture was stirred for 4 hours. The reaction was then rotoevaporated to yield the 3-amino-1-alkyl-1,3,4,5tetrahydro-2H-1-benzazepin-2-one (100% yield).
Example 6-A Synthesis of 3-Amino-1 ,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one Ste 3-Amino-5-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one was prepared from 4-methyl-a-tetralone using the methods described in Armstrong et al. Tetrahedron Letters, 1994, 35, 3239.
Step B: 3-Amino-5-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (9.3g 100M%) was dissolved in dioxane (300mL) and the solution was chilled to 0 0 C. BOC-anhydride (13.89g 130M%) was added and the ice bath was removed allowing the solution to come to room temperature and stirring was continued for 16 hours. The solution was rotory evaporated to remove dioxane to provide an off white solid. This solid was recrystallized from CHC1 3 to yield BOC-protected 3-amino-5-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2one in 55% yield.
Step C: BOC-protected 3-amino-5-methyl-1,3,4,5-tetrahydro-2H-1benzazepin-2-one (100 was dissolved in DMF (20mL) and NaH 100 was added in one portion and the reaction mixture was stirred for 1 hour. Methyl iodide (300 was added and this mixture was stirred for 12 hours. The reaction was then poured into water and extracted with ethyl acetate (3x) then backwashed with water (3x) and then brine Treatment with MgSO 4 rotoevaporation, and chromotography MeOH/CH 2 Cl 2 WO 98/28268 PCT/US97t22986 282 yielded BOC-protected 3-amino-i, 5-dimethyl- 1,3,4, 5-tetrahydro-2H- 1benzazepin-2-one in 75% yield.
Step D: BOC-protected 3-amino-i ,5-dimethyl- 1,3,4 ,5-tetrahydro-2H- 1benzazepin-2-one (100 M was suspended in 30 mL of 1: 1
CH
2 Cl 2 /triflouroacetic acid. The reaction mixture was stirred for 4 hours. The reaction was then rotoevaporated to yield 3-amino-1,5-dimethyl-1,3,4,5tetrahydro-2H- 1-benzazepin-2-one (100% yield).
Example 6-B Synthesis of 5-(L-Alaninyl)-amiino-3,3,7-trimethyl- 5,7-dihydro-6H-benz[blazepin-6-one Hydrochloride Following the procedure of Example 7-1 and using 5-amino-3,3,7-trimethyl- 5, 7-dihydro-6H-benz[b]azepin-6-one hydrochloride (Example the title compound was prepared.
Example 6-C Synthesis of 5-Amino-3,3,7-trimethyl-5,7-dihydro- 6H-benz[b~azepin-6-one Hydrochloride Step A: Following General Procedure 5-A and using N-t-Boc-5-amino-3.3- ,7-dihydro-6H-benz[b~azepin-6-one (General Procedure 6-B, following by Boc protection) and methyl iodide, N-t-Boc-5-amino-3,3,7trimethyl-5 ,7-dihydro-6H-benz[b] azepin-6-one was prepared.
Step B: Following General Procedure 8-N and using N-t-Boc-5 -amino- 3,3, 7-trimethyl-5 ,7-dihydro-6H-benzjlb]azepin-6-one, the title compound was prepared.
WO 98/28268 PCZTIUS97/22986 283 Example 6-D Synthesis of 3-(S)-Amino-1-methyl-5-oxa-1 ,3,4,5tetrahydro-2H-1-benzazepin-2-one Step A: 3-(S)-Amino-5-oxa- 1,3,4, 5-tetrahydro-2H- 1-benzazepin-2-one was prepared from N-Boc-serine (Bachem) and 2-fluoro-l-nitrobenzene (Aldrich) using the method of R. J. DeVita et al., Bioorganic and Medicinal Chemistry Lett. 1995, 5(12) 1281-1286.
Step B Following General Procedure 5-A and using the product from Step A, the title compound was prepared.
Example 6-E Synthesis of 3-(S)-Amino-l-ethyl-5-oxa-1,3,4,5tetrahydro-2H-1-benzazepin-2-one Step A: 3-(S)-Amino-5-oxa- 1,3,4 ,5-tetrahydro-2H- 1-benzazepin-2-one was prepared from N-Boc-serine (Bachem) and 2-fluoro-1-nitrobenzene (Aldrich) using the method of R. J. DeVita et al., Bioorganic and Medicinal Chemistry Lett. 1995, 5(12) 1281-1286.
Step B: Following General Procedure 5-A and using the product from Step A, the title compound was prepared.
Example 6-F Synthesis of 3-(S)-Amino-1-methyl-5-thia-1,3,4,5tetrahydro-2H-1-benzazepin-2-one The title compound was prepared from N-Boc-cystine (Novabio) and 2fluoro-1-nitrobenzene (Aldrich) using the method of R. J. DeVita et al., Bioorganic and Medicinal Chemistry Lett. 1995, 5(12) 128 1-1286, followed by General Procedure WO 98/28268 P CT1US97/22986 284 Example 6-1 Synthesis of 1-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino- 3-methyl-i ,3,4,5-tetrahydro-2H-3-benzazepin-2-one Following General Procedure A above using L-alanine (Example B) and 1-amino-3-methyl-1 ,3,4,5-tetrahydro-2H-3benzazepin-2-one, the title compound was prepared. The reaction was monitored by tlc on silica gel (Rf 0. 15 in ethyl acetate) and purification was by flash chromatography using ethyl acetate as the eluant.
NMR data was as follows: 'H-nmr (CDCI 3 2 diasteromers): 8 8.10 (in, 7.58 7.42 (d.
0.511), 7.05 (in, 41-0, 6.65 (in, 3H), 6.29 (in, IH), 4.80 lH), 4.20 (in, 1H), 3.36 0.5H), 3.34 3.26 (bd, 2H), 3.10 (in, 2H), 3.01 3H), 2.98 3H), 1.36 3H), 1.29 3H1).
'C-nmr (CDCI 3 2 diasteromers): 8 168.2, 167.9, 165.3, 165.2, 165.1, 164.9, 160.3, 160.1, 157.0, 156.8, 134.4, 134.3, 130.1, 129.9, 129.0, 128.8, 126.0, 123.3, 122.5, 119.5, 119.1, 107.9, 107.8, 107.6, 98.3, 98.0, 97.6, 47.6, 47.4, 44.6, 44.5, 43.7, 43.6, 38.0, 37.8, 30.6, 30.5, 26.6, 14.6, 14.1.
C,
2
H
23
N
3 0 3
F
2 (MW 415.44); mass spectroscopy 415.
Example 6-2 Synthesis of 3-ethyl-7-fluoro-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one Following General Procedure C above using alanine (Example B) and 1 -(S)-amino-3-ethyl-7-fluoro- 1,3 ,4,5-tetrahydro-2H-3 benzazepin-2-one (General Procedure the title compound was prepared.
Purification was by flash chromatography using 5% methanol/dichloroinethane as. the eluant.
NMR data was as follows: 'H-nmr (CDCl 3 6 7.8-7.7 (2xd, J 7 Hz, IHO 7.1-7.0 (in, 2H), 6.8 (in, 6.2 1H), 4.7 11H1, 4.2 (in, I 3.6-3.4 (in, 6H), 3.2 (in, 2H), 1.3 (2xd, J 7 Hz, 1.1 (2xt, J 7 Hz, 3H).
WO 98/2868 PCT/US97122986 13C-nmr (CDCl 3 8 177.3, 172.5, 172.1, 169.6, 169.4, 163.8, 160.5, 126.3, 126.2, 125.9, 125.8, 117.4, 117.2, 117.1, 116.9, 113.7, 113.4, 112.4, 112.3, 112.1, 112.0, 103.0, 102.9, 102.7, 102.6, 102.2., 53.3, 51.7, 51.4, 49.2, 49.0, 44.8, 44.5, 42.6, 42.5, 42.4, 42.3, 32.2, 19.0, 13.0, 12.9.
C1 3 H 4
N
3 0 3
F
3 (MW 447.19); mass spectroscopy N/A.
Example 6-4 Synthesis of 3-(N 1,3,4,5-tetrahydro-2H-1-benzazepin-2-one Following General Procedure A above using alanine (Example B) and 3 -amino- 1,3 ,4,5-tetrahydro-2H- 1 -benzazepin-2-one (General Procedure the title compound was prepared. The reaction was monitored by tic on silica gel (Rf 0. 15 in 12% methanol/dichloromethane) and purification was by flash chromatography using 12% methanol/dichioromethane as the eluant.
NMR data was as follows: 'H-nmr (CDCl 3 8 9.87 111), 8.28 1H), 8.11 1H), 7.30 6.96 (in, 7H), 4.23 (in, 111), 4.18 (in, 1H), 3.49 2H), 2.68 (mn, 2H), 2.24 (mn, 1H), 1.97 (in, 111), 1.15 3H1).
3 C-nmr (CDC1 3 6 171.95, 171.54, 189.00, 160.74, 141.06, 138.01, 133.91, 129.90, 127.84, 125.58, 122.41, 112.79, 112.46, 102.23, 49.06, 48.47, 41.67, 35.50, 28.39, 18.99.
C,,H,,N
3
O
3
F
2 (MW 401.42); mass spectroscopy 402.
Example Synthesis of 3-(N 1 -benzyl-1 ,3,4,S-tetrahydro-2H-3-benzazepin-2-one Following General Procedure A above using alanine (Example B) and 3 -amino- I -benzyl I ,3,4,5-tetrahydro-2H-3 -benzazepin- 2-one (General Procedure the title compound was prepared. Purification was by flash chromatography.
WO 98/28268PcTS9/28 PCTIUS97/22986 286 NMR data was as follows: t H-nmr (CDCl 3 2 diasteromers): 8 7.20 (in, 9H), 6.73 (in, 3H), 5.26 (dd, lH), 4.76 (dd, 111), 4.53 111), 4.44 (mn, 1H), 3.44 IH), 2.40 (in, 3H), 1.83 (mn, 1H), 1.28 (dd, 3H).
1 3 C-nmr (CDCl 3 2 diasteromers): 6 172.2, 172.1, 171.2, 171.1, 170.0, 169.8, 1565.2, 165.0, 162.0, 140.7, 139.2, 137.4, 136.6, 129.9, 129.1, 128.9, 128.7, 128.5, 128.1, 127.6, 124.0, 112.9, 112.8, 112.7, 112.6, 103.4, 103.1, 102.8, 52.6, 52.5, 50.3, 49.5, 49.4, 43.1, 36.6, 36.5, 28.7, 28.6, 19.4, 19.2.
C,
8
H
27
N
3 0 3
F
2 (MW 491.54); mass spectroscopy 491.
Example 6-7 Synthesis of 1-methyl-1,3,4,5-tetrahydro-2H-1 -benzazepin-2-one Following General Procedure A above using alanine (Example B) and 3-(S)-amino- 1-methyl-I ,3,4,5-tetrahydro-2H- 1benzazepin-2-one (General Procedure the title compound was prepared.
The reaction was monitored by tic on silica gel (Rf 0.21 in 3% inethanol/dichloromethane) and purification was by flash chromatography using 3% methanol/dichloroinethane as the eluant.
NMR data was as follows: 'H-nmr (CDCl 3 86 7.20 (in, 4H), 6.86 1H), 6.68 (in, 3H), 6.33 (d, IH), 4.40 (mn, 3H), 3.46 2H), 3.36 3H), 2.78 (in, 2.57 (in, 2H), 1.84 (mn, 111), 1.29 3H).
1 3 C-nmr (CDC1 3 6 171.5, 171.0, 169.4, 165.3, 165.1, 162.0, 161.8, 141.9, 138.7, 135.1, 129.9, 128.6, 127.5, 123.4, 113.0, 112.5, 103.6, 103.3, 103.0, 50.4, 49.5, 43.5, 36.7, 36.1, 28.8, 19.5.
C,,H,
3
N
3 0 3 F, (MW 415.44); mass spectroscopy 415.
Example 6-8 Synthesis of 3-(N 1 ,5-dimethyl-1 ,3,4,5-tetrahyd ro-2 H- 1-benzazepin-2-one WO 98/28268 PCT/US97/22986 287 Following General Procedure C above using alanine (Example B) and 3-amino- 1,5-dimethyl-1,3,4,5-tetrahydro-2H- 1benzazepin-2-one (prepared from 4-methyltetralone (Aldrich) using General Procedure the title compound was prepared as a solid having a melting point of 115-119°C. Purification was by flash chromatography using methanol/dichloromethane as the eluant.
NMR data was as follows: 'H-nmr (CDCI 3 6 7.2-7.0 5H), 6.8-6.5 4H), 4.5 J 7 Hz, 1H), 4.3 J 4 Hz, 1H), 3.5 2H), 3.35 3H), 3.05 J 6.5 Hz, 1H), 2.2 J 4.5 Hz, 1H), 1.95 1H), 1.3 (2xd, J 7 Hz, 6H).
"C-nmr (CDCl 3 6 172.3, 166.4, 165.9, 164.4, 164.3, 160.0, 159.9, 156.6, 139.9, 136.4, 133.6, 133.2, 122.8, 122.4, 120.5, 118.1, 107.6, 107.3, 98.2, 97.9, 97.5, 95.5, 45.0, 44.9, 44.0, 43.9, 39.8, 39.7, 37.9, 30.7, 30.7, 26.0, 14.0, 13.8, 12.4.
C,
3
H,
5
N
3 0 3
F
2 (MW 429.47); mass spectroscopy 430.
Example 6-9 Synthesis of 3-(3,5-Difluorophenylacetyl)amino- 1,5-dimethyl-l,3,4,5-tetrahydro-2H-1-benzazepin-2-one Following General Procedure C above using acid (Oakwood) and 3-amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin- 2-one (Example the title compound was prepared as a solid having a melting point of 185-187°C. Purification was by flash chromatography using 5% methanol/dichloromethane as the eluant.
NMR data was as follows: 'H-nmr (CDCl 3 6 7.4-7.1 4H), 6.9-6.6 4H), 4.3 J 8 Hz, 1H), 3.5 2H), 3.35 3H), 3.05 J 6.5 Hz, 1H), 2.3 J 8 Hz, 1H), 1.95 J 7 Hz, 1H), 1.3 J 7.1 Hz, 3H).
"1C-nmr (CDCl 3 6 166.1, 163.8, 160.0, 159.8, 156.7, 156.5, 136.4, 133.8, 133.7, 133.3, 122.8, 122.5, 120.5, 118.1, 107.6, 107.5, 107.3, 107.2, 98.2, 97.8, 97.5, 45.1, 39.9, 38.0, 30.6, 26.0, 12.5.
WO 9W28268 PCTIUS97/22986 288 C2 0
H
2 ON20,F 2 (MW 358.39); mass spectroscopy 359.
Example 6-10 Synthesis of -(3,5-Dif Iuorophenylacetyl)-L-alaninyl) amino- 1-methyl-5-oxa-1 ,3,4,5-tetrahydro-2H-1-benzazepin-2-one Following General Procedure A above using N-(3 L-alanine (Example B) and 3-(S)-amino-1-methyl-5-oxa-1 ,3,4,5-tetrahydro-2H- 1-benzazepin-2-one (Example the title compound was prepared as a solid having a melting point of 1 10- 1 14*C. The reaction was monitored by tic on silica gel (Rf 0.38 in 10% methanol/dichloromethane) and purification was by silica gel chromatography.
NMR data was as follows: 'H-nmr (CDCl 3 8 7.25 J=4.2, 1H); 7.2 (in, 4H); 6.79 J=5.7, 211), 6.70 J=2.1, 2.1, 1H); 6.61 J=7.5, 1H); 4.83 (dq, J=7.2, 11.1, 1H); 4.55 (dt, J=7.8, 9.3, 5.1, 211); 4.11 (dd, J=9.9, 11.1, 1H1); 3.48 (s, 2H); 3.39 311); 1.30 J=6.6, 3H).
1 3 C-nmr (CDCl 3 8 167.3, 164.4, 160.0, 156.7, 145.2, 133.5, 131.2, 122.9, 120.9, 118.5, 118.1, 107.6, 107.4, 98.3, 37.9, 37.6, 44.5, 44.0, 37.8, 36.6, 14.0.
C
21
H
2 jF 2
N
3 0 4 (MW 417); mass spectroscopy 418.
Example 6-11 Synthesis of 1-ethyl-5-oxa-1 ,3,4,5-tetrahydro-2H- 1-benzazepin-2-one Following General Procedure A above using alanine (Example B) and 3-(S)-ainino- 1-ethyl-5-oxa- 1,3 ,4,5-tetrahydro-2H- 1benzazepin-2-one (Example the title compound was prepared as a solid having a melting point of 188-191'C. The reaction was monitored by tic on silica gel (Rf 0.43 in 10% methanol/dichloromethane) and purification was by recrystallization from ether/hexanes.
NMR data was as follows: WO 98t28268 PCT1US97/22986 289 'H-nnir (CDC1 3 6 7.2 (in, 4H); 7.1 (mn, 111); 6.79 (dcl, J=6.0, 6.6, 2H); 6.71 J=2.2, 2.2, 1H); 6.43 (cid, J=7.2, 8.8, 1H); 4.8 (mn, 1H); 4.6 (in, 2H); 4.2 (in, 2H); 3.50 2H); 1. 31 (cd, J 3H); 1. 16 J 7. 1, 3H).
3 C-nr (CDC1 3 6 172.9, 167.5, 164.8, 164.3, 146.6, 130.2, 123.6, 121.4, 119.3, 118.5, 108.0, 107.7, 98.4, 44.9, 44.4, 39.0,;38.3, 14.3.
C
22
H
23
F
2
N
3 0 4 (MW 431); mass spectroscopy (MW) 432.
Example 6-12 Synthesis of 3-(S)-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino- 1 -methyl-5-thia- 1,3,4,5-tetrahydro-2H-1 -benzazepin-2-one Following General Procedure A above using alanine (Example B) and 3-(S)-amino-l1-methyl-5-thia- 1,3 ,4,5-tetrahydro-2H- 1benzazepin-2-one (Example the title compound was prepared as a solid having a melting point of 156-159'C. The reaction was monitored by tic on silica gel (Rf =0.17 in 10% methanol/dichloroinethane) and purification was by silica gel chromatography.
NMR data was as follows: 'H-nmr (CDCl 3 .5 7.63 J=6.05, 1H); 7.43 J=7.7, 7.7. 1H); 7.2 (in, 311); 6.79 (di, J=6.05, 2H); 6.54 J=7.1, 7.1, LH); 6.35 (di, J=7.7, 1H); 4.5 (in, 2H); 3.7 (mn, 1H); 2.79 J=11.0, 11.5, 1H); 1.29 J=6.6, 3H).
1 3 C-ninr (CDCI 3 6 172.9, 166.8, 165.8, 164.7, 141.4, 133.8, 131.4, 126.2, 123.4, 122.7, 120.2, 108.0, 107.7, 98.4, 45.3, 44.5, 40.1, 38.3, 33.8, 32.0, 14.3.
C,
1
H
21
F
2
N
3 0 3 S (MW 433); mass spectroscopy 434.
Example 6-13 Synthesis of IN'-(3,5-Difluoroph enylacetyl)-L-alaninyl) -amnino- 3,3-dimethyl-5,7-dihydro-6H-benz[bJ azepin-6-one WO 98/28268 PCT1US9722986 290 Following General Procedure D and using alanine (Ex. B) and 5-amino-3 ,3-dimethyl-5 ,7-dihydro-6H-benzb]azepin-6-one, the title compound was prepared. The reaction was monitored by tlc (Rf 0. 1, MeOHICHCl 3 and product was purified by chromatography (silica, 6% MeOHICHC 3 NMR data was as follows: 'H-nmr (d 6 -DMSO): 56 3.50 9.55 (d,lH).
MW 429.47; mass spectroscopy 429.
Example 6-14 Synthesis of (N'-(3,5-Difluorophenylacetyl)-L-alaninyl) amino- 3,3,7-trimethyl-5,7-dihydro-6H-benzfbj azepin-6-one Following General Procedure D and using alanine (Ex. B) and 5-amino-3,3 ,7-trimethyl-5 ,7-dihydro-6H-benz[bjazepin-6-one hydrochloride (Example the title compound was prepared. The reaction was monitored by tlc (RI 0.4, 5% MeOH/CHCI 3 and product was purified by chromatography (silica, 5% MeOII/CHC 3 and crystallization from acetonitrile.
NMR data was as follows: 'H-nmr (d 6 -DMSO): 8 3.48 4.25 MW 443.50; mass spectroscopy 443.
Example 6-15 Synthesis of 5-{N'-[S)-3,5-Difluoromandelylj -L-alaninyl) amino- 3,3,7-trimethyl-5,7-dihydro-6H-benzlbl azepin-6-one Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-alaninyl)-amino-3 ,3 ,7-trimethyl-5 ,7-dihydro-6Hbenz[blazepin-6-one hydrochloride (Example the title compound was prepared. The product was purified by chromatography (silica, 3% MeOH/CHC 3 NMR data was as follows: 'H-nmr (CDCI 3 6 3.35 3H); 5.07 111).
WO 9828268PCTIUS97/22986 291 MW 459.49; mass spectroscopy 460.
Example 6-16 Synthesis of 1-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino- 5-phenyl-1 ,3,4,5-tetrahydro-2H-3-benzazepin-2-one Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood) and 1 ,5-difluorophe l,3,4,5-tetrahydro-2H-3-benzazepin-2-one, the title compound was prepared.
Purification was by. LC 2000 chromatography using ethyl acetate as the eluant.
C
27
H.,
5
N
3 0 3
F
2 (MW 477); mass spectroscopy 478.1.
Anal. Cale. for C 2 7
H
25
N
3 0 3
F
2 C, 67.91; H, 5.28; N, 8.8. Found: C, 68.2; H, 5.35; N, 8.58.
Example 6-17 Synthesis of 3-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amino- 1-ethyl-5,5-dixnethyl- 1,3,4,5-tetrahydro-2H-1-benzazepin-2-one Following General Procedure C above using alanine (Example B) and 3 -amino- I -ethyl-5,5 -dimethyl- 1,3,4,5 -tetrahydro-2H- I benzazepin-2-one (General Procedure the title compound was prepared.
The reaction was monitored by tic (Rf 0.23, 30% EtOAc/hexanes) and the product was purified by flash chromatography using EtOAc/hexanes as the eluant.
NMR data was as follows: 'H-rnr (CDCl 3 85 7.1-7.4 (in, 6H), 6.70 (in, 2H), 6.62 lH), 4.46 (in, 1H), 4.39 (mn, 114), 3.64 (in, 1H), 3.57 2H), 2.52 (mn, lH), 1.90 (in, 1H), 1.30 (mn, 12H).
1 3 C-nmr (CDCI 3 '5 167.3, 167.2, 165.7, 165.0, 164.9, 160.2, 160.1, 156.9, 156.8, 136.4, 136.3, 134.5, 134.4, 123.4, 122.5, 122.0, 119.7, 107.9, 107.8, 107.6, 97.9, 97.8, 45.5, 44.9, 44.9, 44.37, 44.34, 40.0, 39.9, 37.9, 30.6, 36.7, 24.4, 14.2, 14.1, 9.15, 9.12.
C,-
4
H.,
9
N
3 0 3 F, (MW 457.52); mass spectroscopy N/A.
WO 98/28268 PCT/US97/22986 292 Example 6-18 Synthesis of 3-(3,5-Difluorophenylacetyl)amino- 1 -ethyl-5,5-dimethyl- 1,3,4,5-tetrahydro-2H-1-benzazepin-2-one Following General Procedure C above using acid (Oakwood) and 3 -amino- I -ethyl-5,5-dimethyl- 1,3 ,4,5-tetrahydro-2H- 1 benzazepin-2-one .(General Procedure the title compound was prepared.
The reaction was monitored by tic (Rf 0.28, 25% EtOAc/hexanes) and the product was purified by flash chromatography using EtOAc/hexanes as the eluant.
NMR data was as follows: 'H-rnr (CDCl 3 8 7.38 1H), 7.20 (in, 4H), 6.81 2H), 4.42 (mn, IH), 3.95 (in, 1H), 3.70 (in, 1H), 3.29 2H), 2.45 (mn, 1H), 1.38 3H), 1.30 3H1), 1.24 3H).
3 C-rnr (CDCl 3 8 166.2, 164.2, 160.3, 160.1, 157.0, 156.8, 136.5, 136.3, 134.3, 123.4, 122.6, 122.1, 119.8, 107.9, 107.8, 107.7, 107.6, 98.4, 98.0, 97.7, 45.7, 44.9, 40.0, 38.2, 36.6, 26.8, 24.5, 9.2.
2 0 2 F2 (MW 386.45).
Example 6-19 Synthesis of 3-(N'-(Cyclopentylacetyl)amino- 1-ethyl-5,5-dimethyl-1 ,3,4,5-tetrahydro-2H-1-benzazepin-2-one Following General Procedure C above using N-(cyclopentylacetyl)-Lalamine (Example D) and 3 -amino-i1 -ethyl-S ,5-triinethyl- 1, 3,4, 5-tetrahydro-2H- 1-benzazepin-2-one (General Procedure the title compound was prepared.
The reaction was monitored by tlc (Rf 0.25, 30% EtOAc/hexanes) and the product was purified by flash chromatography using EtOAc/hexanes as the eluant.
NMR data was as follows: 'H-ninr (CDCI 3 8 7.3 8 IlH), 7.20 (in, IlH), 6.42 I 4.43 (in, 1H), 3.93 (in, 11H), 3.83 (in, lH), 2.42 (in, 1H), 2.19 2H), 1.68 (in. 2H), 1.50 (in, 2H), 1.35 3H1), 1.22 3H), 1.21 3H), 1.05 (in, 211).
WO 98/28268 PCTIUS97/22986 293 3 C-nmr (CDC1 3 6 168.1, 168.0, 167.16, 167. 11, 165.7, 136.5, 136.4, 123.3, 122.52, 122.50, 122.14, 122.1, 119.8, 119.7, 55.8, 45.6, 45.5, 44.8, 44.7, 44.08, 44.05, 40.07, 40.01, 38.1, 32.5, 30.67, 30.65, 27.9, 27.8, 26.8, 24.5, 20.3, 14.37, 14.32, 9.58, 9.2, 9.1.
C,
4
H
35
N
3 0 3 (MW 413.56); mass spectroscopy (MH) N/A.
7. Dibenzazepinone Derivatives and Related Compounds GENERAL PROCEDURE 7-A Preparation of 5-Amino-7-alkyl-5,7-dihydro- 6H-dibenz[b,dlazepin-6-one Derivatives Step A: Following General Procedure 5-A and using 5,7-dihydro-6Hdibenz[b,d]azepin-6-one and an alkyl halide, the 7-alkyl-5,7-dihydro-6Hdibenz[b,d]azepin-6-one was prepared.
Step B: The 7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1 eq.) was dissolved in THF and isoamylnitrite (1.2 eq.) was added. The mixture was cooled to 0°C in an ice bath. NaHMDS (1.1 eq., 1M in THF) was added dropwise. After stirring for 1 hour or until the reaction was complete, the mixture was concentrated then acidified with 1N HCI and extracted with EtOAc. The organic portion was dried and concentrated to yield a crude product which was purified by silica gel chromatography.
Step C: The resulting oxime was dissolved in EtOH/NH 3 (20:1) and hydrogenated in a bomb using Raney nickel and hydrogen (500 psi) at 100°C for 10 hours. The resulting mixture was filtered and concentrated to provide an oil which was purified by silica gel chromatography to yield the title compound.
GENERAL PROCEDURE 7-B Preparation of Fluoro-substituted 5,7-dihydro-6Hdibenz[b.dlazepin-6-one Derivatives WO 98/28268 PCT/US97/22986 294 A modification of the procedure of Robin D. Clark and Jahangir, Tetrahedron, Vol. 49, No. 7, pp. 1351-1356, 1993 was used. Specifically, an appropriately substituted N-t-Boc-2-amino-2'-methylbiphenyl was dissolved in THF and cooled to -78°C. s-Butyl lithium (1.3M in cyclohexane, 2.2 eq.) was added slowly so that the temperature remained below -65 C. The resulting mixture was allowed to warm to -25*C and was stirred at that temperature for 1 hour. The mixture was cooled to -78*C. Dry CO 2 was bubbled through the mixture for 30 seconds. The mixture was allowed to warm to ambient temperature then was carefully quenched with water. The mixture was concentrated under reduced pressure then was adjusted to pH 3 with IN HCI.
The mixture was extracted with EtOAc and the organic portion was dried and concentrated to yield a crude material. The crude material was dissolved in methanol and the solution was saturated with HC1. The mixture was heated at reflux for 12 hours then was allowed to cool. The mixture was concentrated to provide crude lactam which was purified by chromatography or crystallization.
GENERAL PROCEDURE 7-C Resolution of 5-Amino-7-methvl-5.7-dihvdro-6H-dibenz[b.dlazepin-6-one In a round bottom flask was added the racemic freebase amine (1.0 eq.) in methanol followed by di-p-toluoyl-D-tartaric acid monohydrate (1.0 The mixture was concentrated in vacuo to a residue and redissolved in a moderate volume of methanol and allowed to stir at room temperature open to the atmosphere (8-72 hours). The solid was removed by filtration. The enantiomeric excess was determined by chiral HPLC (Chiracel ODR) using acetonitrile and 85% H20 with 0.1% trifluoroacetic acid and a flow rate of 1.0 mL/min at 35 C. The resolved di-p-toluoyl-D-tartaric salt was then dissolved in EtOAc and saturated NaHCO 3 until pH 9-10 was reached. The layers were separated and the organic layer was washed again with saturated NaHCO 3 HzO, and brine. The organic layer was dried over MgSO, and the drying agent was removed by filtration. The filtrate was concentrated in vacuo.
The free amine was dissolved in MeOH and HCI (12M, 1.0 eq.) was added.
WO 98/28268 PCT/US97/22986 295 The salt was concentrated in vacuo and the resulting film was triturated with EtOAc. The HCI salt was filtered and rinsed with EtOAc. The ee was determined by chiral HPLC.
Example 7-A Synthesis of 5-Amino-7-methyl-5,7-dihydro- 6H-dibenz[b,d]azepin-6-one Hydrochloride Step A Synthesis of 7-Methyl-5.7-dihvdro-6H-dibenz[b.dlazepin-6-one A round bottom flask was charged with sodium hydride (0.295 g, 7.46 mmol) in 9.0 ml of DMF and treated with 5,7-dihydro-6H-dibenz[b,d]azepin-6one (1.3 g, 6.22 mmol) (CAS 20011-90-9, prepared as described in Brown, et. al., Tetrahedron Letters, No. 8, 667-670, (1971) and references cited therein). After stirring at 60°C for 1 h, the solution was treated with methyl iodide (1.16 ml, 18.6 mmol) and stirring continued for 17 h with the exclusion of light. After cooling, the reaction was diluted with CH 2 Cl 2
/H
2 0, washed with NaHSO 4 solution, H 2 0, and dried over Na 2
SO
4 Evaporation and flash chromatography (SiO 2 CHC1 3 gave 0.885 g of the title compound as a colorless solid.
NMR data was as follows: 'H-nmr (CDC13): 6 7.62 2H), 7.26-7.47 6H), 3.51 2H), 3.32 3 H).
C,,H,
3 NO (MW 223.27); mass spectroscopy 223.
Anal. Calcd for C,,H, 3 NO; C, 80.69 H, 5.87 N, 6.27. Found: C, 80.11 H, 5.95 N, 6.23.
Step B Synthesis of 7-Methyl-5-oximo-5.7-dihydro-6Hdibenz[b,d]azepin-6-one The compound isolated above (0.700 g, 3.14 mmol) was dissolved in 20 ml of toluene and treated with butyl nitrite (0.733 ml, 6.28 mmol). The reaction temperature was lowered to 0°C and the solution was treated with KHMDS WO 98/28268 PTU9128 PCTIUS97/22986 296 (9.42 ml, 0.5 M) under N, atmosphere. After stirring for 1 h the reaction was quenched with a saturated solution of NaHSO 4 diluted with CH,Cl, and separated. The organic layer was dried over Na.,S0 4 and the title compound purified by chromatography (SiO, 98:2 CI-C1 3 /MeOH) giving 0.59 g (80 as a colorless solid.
C,
5
H,
2 N2O, (MW 252.275); mass spectroscopy 252.
Anal. Calcd for C, 5
H
1 2
N
2 0 2 C, 71.42 H, 4.79 N, 11. 10. Found: C, 71.24 H, 4.69 N, 10.87.
Step C Synthesis of 5-Amino-7-Methvl-5,7-dihydro-6Hdibenz[b~dlazepin-6-one Hydrochloride The oxime isolated above (0.99 g, 3.92 mmol) was hydrogenated in a Parr apparatus at 35 psi over 10 Pd/C (0.46 g) in 3A ethanol. After 32 h the reaction mixture was filtered through a plug of celite, the filtrate evaporated to a foam and treated with a saturated solution of HCl in Et,O. The resulting colorless solid was filtered, rinsed with cold Et 2 O and vacuum dried to give 0.66 g (61 of the title compound.
NMR data was as follows: 'H-nmr (DMSOd6): 6 9.11 (bs, 3H), 7.78-7.41(m, 8H), 4.83 IR), 3.25 3 H).
C
15
H,
4 N,O. HCl (MW 274.753); mass spectroscopy (MH+ free base) 238.
Anal. Calcd for C, 5
H
14
N
2 0. HCI; C, 65.57 5.50 N, 10. 19 Found: C, 65.27 H, 5.67 N, 10.13.
Example 7-B Synthesis of and (R)-5-(L-Alaninyl)-amino-7-methyl- 5,7-dihydro-6H-dibenzlb,dI azepin-6-one Step A Synthesis of and (R)-5-(N-Boc-L-Alaninyl)-amino-7methyl-5.7-dihydro-6H-dibenzrb~dlazepin-6-one Boc-L-Alanine (0.429 g, 2.26 mmol) (Aldrich) was dissolved in THF and treated with HOBt hydrate (0.305 g, 2.26 minol), and 5-amino-7.-methyl-5,7dihydro-6H-dibenz[b,d~jazepin-6-one (0.45 g, 1.89 mmol) (Example The WO 98/28268 PCT/US97/22986 297 temperature was lowered to 0°C and the reaction mixture treated with EDC (0.449 g, 2.26 mmol) (Alrich) and stirred 17 hours under The reaction mixture was evaporated, the residue diluted with EtOAc/H,O, washed 1.0 N HC1, sat. NaHC0 3 brine and dried over Na 2 SO4. The diastereomers were separated on a Chiralcel OD column using 10% IPA/heptane at 1.5 ml/minute.
Isomer 1: Retention time 3.37 minutes.
NMR data was as follows: 'H-nmr (CDCl1): 6 7.62-7.33 9H), 5.26 1H), 5.08 1H), 4.34 1H), 3.35 3H), 1.49 9H), 1.40 3H).
Optical Rotation: [a] 20 96 589 nm (c 1, MeOH).
C,
3
H,
7
N
3 0 4 (MW 409.489); mass spectroscopy 409.
Anal. Calcd for C 23
H
2 7
N
3 0 4 C, 67.46 H, 6.64 N, 10.26. Found: C, 68.42 H, 7.02 N, 9.81.
Isomer 2: Retention time 6.08 minutes.
NMR data was as follows: 'H-nmr (CDCl 3 6 7.74 (bd,1H), 7.62-7.32 8H), 5.28 1H), 4.99 1H), 4.36 1H), 3.35 3H), 1.49 9H), 1.46 3H).
Optical Rotation: [a]2 0 69 589 nm (c 1, MeOH).
C
23
H,
7
N
3 0 4 (MW 409.489); mass spectroscopy 409.
Anal. Calcd for C 23
H
27
N
3 0 4 C, 67.46 H, 6.64 N, 10.26. Found: C, 67.40 H, 6.62 N, 10.02 Step B Synthesis of and (R)-5-(L-Alaninvl)-amino-7-methvl-5,7dihvdro-6H-dibenz[b,dlazepin-6-one Hydrochloride The compounds isolated in Part A (each isomer separately) were dissolved in dioxane and treated with excess HCI After stirring for 17 hours, the title compounds were isolated as colorless solids after evaporation and vacuum drying.
Isomer 1:
C
8 ,Hi 9
N
3 0,.HCI (MW 345.832); mass spectroscopy (MH+ free base) 309.
Optical Rotation: [a]20 55 589 nm (c 1, MeOH).
Isomer 2: WO 98/28268PcTS9I98 PCTIUS97/22986 298 C,gHl 9
N
3 0,-.HC1 (MW =345.832); mass spectroscopy (MH+ free base) 309.
Optical Rotation: [a 20 80 589 nm (c 1, MeOH).
Example 7-C Synthesis of and (R)-5-(L-Valinyl)-amino-7-methyl- 5,7-dihydro-6H-dibenz[b,dJ azepin-6-one Step A Synthesis of and (R)-5-(N-Boc-L-Valinyl)-amino-7methyl-S .7-dihydro-6H-dibenz[b~dlazenin-6-one Boc-L-Valine (0.656 g, 3.02 minol) (Aldrich) was dissolved in THF and treated with HOBt hydrate (0.408, 3.02 mmol), Dipea (1.05 ml, 6.05 mmol) and 5-amino-7-methyl-5 ,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (0.75 g, 2.75 mmol)(Example The temperature was lowered to 0 0 C and the reaction mixture treated with EDC (0.60 1 g, 3.02 mmol)(Alrich) and stirred 17 hours under The reaction mixture was evaporated, the residue diluted with EtOAc/l- 2 0, washed 1.0 N HCl, sat. NaHCO 3 brine and dried over Na 2
SO
4 The diastereomers were separated on a Chiralcel OD column using IPA/heptane at 1.5 mi/minute.
Isomer 1: Retention time 3.23 minutes.
Optical Rotation: [a] 20 =-120 589 nmn (c MeOH).
C,
5
H
3
,N
3 0 4 (MW 437.544); mass spectroscopy 438 Isomer 2: Retention time 6.64 minutes.
Optical Rotation: [a]20 50 589 nm (c 1, MeOH).
C
25
H
3
,N
3 0 4 (MW 437.544); mass spectroscopy 438 Step B Synthesis of and (R)-5-(L-Valinyl)-amino-7-methyl-5.7dihydro-6H-dibenz[b~dlazenin-6-one Hydrochloride The compounds isolated in Part A (each isomer separately) were dissolved in dioxane and treated with excess HIi After stirring for 17 hours, the title compounds were isolated as colorless solids after evaporation and vacuum drying.
Isomer 1:
C,
0
H,
3
N
3 0,-.HCI (MW 373.88); mass spectroscopy (MH+ free base) 338.
WO 98M2268 PCTIUS97/22986 299 Optical Rotation: 38 589 nm (c 1, MeOH).
Isomer 2:
C,
0
H.,
3
N
3 0,.HC1 (MW 373.88); mass spectroscopy (MH+ free base) 338.
Optical Rotation: [a]20 97 589 nm (c 1, MeOH).
Example 7-D Synthesis of and (R)-5-(L-tert-Leucine)-amino-7-methyl- 5,7-dihydro-6H-dibenz[b,dazepin-6-one Step A Synthesis of and (R)-5-(N-Boc-L-tert-Leucinyl)-amino-7methyl-5,7-dihydro-6H-dibenz[b~dlazepin-6-one Boc-L-tert-Leucine (0.698 g, 3.02 mmol) (Fluka) was dissolved in THF and treated with HOBt hydrate (0.408, 3.02 mmol), Dipea (1.05 ml, 6.05 mmol) and 5-amnino-7-methyl-5,7-dihydro-6H-dibenz[b,djazepin-6-one hydrochloride (0.75 g, 2.75 mmol)(Example The temperature was lowered to 0 0 C and the reaction mixture treated with EDC (0.601 g, 3.02 mmol) (Airich) and stirred 17 hours under N 2 The reaction mixture was evaporated, the residue diluted with EtOAcIH,O, washed 1.0 N HCI, sat. NaHCO 3 brine and dried over 4 The diastereomers were separated on a Chiralcel OD column using 10% IPA/heptane at 1.5 ml/minute.
Isomer 1: Retention time 3.28minutes.
Optical Rotation: [a120 -128 589 rn (c 1, MeOH).
C,
6
H
33
N
3 0 4 (MW 451.571); mass spectroscopy 452 Isomer 2: Retention time 5.52 minutes.
Optical Rotation: [a] 20 26 589 rn (c 1, MeOH).
C,
6
H
3 3
N
3 0 4 (MW 451.571); mass spectroscopy 452 Step B Synthesis of and (R)-5-(L-tert-Leucinvl)-amino-7-methvl- 5,7-dihydro-6H-dibenz[b~dlazenin-6-one Hydrochloride The compounds isolated in Part A (each isomer separately) were dissolved in dioxane and treated with excess HCl After stirring for 17 hours, the title WO 98/28268 PCTIUS97/22986 300 compounds were isolated as colorless solids after evaporation and vacuum drying.
Isomer 1: C2,
H
2,N 3 02.HCI (MW 387.91); mass spectroscopy (MH+ free base) 352.
Optical Rotation: [a] 20 34 589 nm (c 1, MeOH).
Isomer 2:
C
21 ,H2N 3 02.HCI (MW 387.91); mass spectroscopy (MH+ free base) 352.
Optical Rotation: [a] 2 0 108 589 nm (c 1, MeOH).
Example 7-E Synthesis of 5-(N-Boc-Amino)-5,7-dihydro-6H,7H-dibenz[b,d]azepin-6-one Step A Synthesis of 5-Iodo-5.7-dihydro-6H-dibenz[b,dlazepin-6-one A solution of 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1.0 g, 4.77 mmol) (Example 7-A) and Et 3 N 2.66 ml, 19.12 mmol) were stirred for 5.0 minutes at 0 C in CHCl 2 and treated with TMSI (1.36 ml, 9.54 mmol). After stirring for minutes 12 (1.81 g, 7.16 mmol) was added in a single portion and the reaction allowed to warm to 5-10 0 C over 3 h. The reaction was quenched with sat. NaSO0 3 diluted with CH 2 C1, and separated. The organics were washed with NaSO3 and NaHSO 3 and dried over MgSO 4 After filtration, the organics were concentrated to approximately 20 ml and diluted with an additional 20 ml of hexanes. The title compound was isolated as a tan precipitate by filtration.
Step B Synthesis of 5-Azido-5,7-dihydro-6H-dibenz[b,dlazepin-6-one The iodide isolate above was dissolved in DMF and treated with 1.2 equivalents of NaN 3 After stirring 17 h at 23 0 C the mixture was diluted with EtOAc/HO, separated, washed with brine and dried over MgSO 4 The title compound was triturated from hot EtOAc as a tan powder.
Step C Synthesis of 5-(N-Boc-Amino)-5,7-dihydro-6H,7Hdibenzrb,dlazepin-6-one WO 98/28268 PCT/US97/22986 301 The azide was dissolved in THF/HO and stirred at 23 0 C for 17 h in the presence of 3.0 equivalents of Ph 3 P. The reaction was diluted with 50 HOAc/toluene, separated, the aqueous layer extracted with toluene and evaporated to an oily residue. This was taken to pH 7.0 by the addition of 1 N NaOH, the resulting HOAc salt was collected and vacuum dried. Finally, the compound was treated with Boc anhydride (1.05 equivalents) and Et 3 N (2.1 equivalents) in THF. After stirring for 5 h at 23 0 C the reaction was filtered and the title compound isolated as a colorless powder.
Example 7-F Synthesis of 5-Amino-7-(2-methylpropyl)-5,7-dihydro- 6H-dibenz[b,d]azepin-6-one Hydrochloride Step A Synthesis of 5-(N-Boc-Amino)-7-(2-methylpropvl)-5,7dihydro-6H-dibenz[b,dlazepin-6-one A solution of 5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6one (0.2g, 0.617 mmol) (Example 7-E) in DMF was treated with Cs 2
CO
3 (0.22 g, 0.678 mmol) and warmed to 60 0 C. To the reaction mixture was added 1iodo-2-methylpropane (0.078 ml, 0.678 mmol) and stirring continued for 17 h.
After cooling to 23 °C the mixture was diluted with CHC1,, washed with several portions of brine and dried over Na,SO 4 The title compound was purified by chromatography (SiO 2 CHCl 3 /MeOH 9:1).
C
23
H
28
N
2 0 3 (MW 380.41); mass spectroscopy 381 Anal. Calcd for C 23
H,
8 N20 3 C, 72.61 H, 7.42 N, 7.36. Found: C, 72.31 H, 7.64 N, 7.17.
Step B Synthesis of 5-Amino-7-(2-methvlpropvl)-5,7-dihvdro-6Hdibenz[b.dlazepin-6-one Hydrochloride The compound isolated in Part A was deprotected in dioxane saturated with gaseous HC1. The title compound was isolated as a slightly colored solid after evaporation and vacuum drying.
WO 98/8268 PCT/US97I22986 302 Example 7-G Synthesis of 5-Amino-7-(methoxyacetyl)-5,7-dihydro- 6H-dibenzib,dlazepin-6-one Hydrochloride Step A- Synthesis of 5-(N-Boc-Amino)-7-(methoxyacetyl)-5,7dihvdro-6H-dibenzfb~dlazepin-6-one A solution of 5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,djazepin-6one (1.03, 3.08 mmol) (Example 7-E) in DMF was treated with CSIC0 3 (1.10 9, 3.39 mmol) and warmed to 60'C. To the reaction mixture was added bromomethyl acetate (0.321 ml, 3.39 mmol) (Aldrich) and stirring continued for 17 h. After cooling to 23 *C the mixture was diluted with CHCI.,, washed wi -th several portions of brine and dried over NaS50 4 The title compound was purified by chromatography (SiO.2, CHCI 3
C,
2
H
24 N,0 5 (MW 396.44); mass spectroscopy 397 Anal. Calcd for C 22
H
24
N
2 0 5 C, 66.65 H, 6.10 N, 7.07. Found: C, 66.28 H, 5.72 N, 6.50.
Step B Synthesis of 5-Amino-7-(methoxvacetl)-5,7-dihydro-6H.
dibenzfb~dlazepin-6-one Hydrochloride The compound isolated in Part A was deprotected in dioxane saturated with gaseous HCI. The title compound was isolated as a colorless solid after evaporation and vacuum drying.
C
17
HI
6 N,0 3 HCI (MW =332.78); mass spectroscopy (MH+ free base) 297.
Example 7-H Synthesis of 5-Amino-7-(3,3-dimethyl-2-butanonyi)- 5,7-dihydro-6H-dibenz~b,djazepin-6-one Hydrochloride Step A- Synthesis of 5-(N-Boc-Amino)-7-(3 .3-dimethyl-butanonyl)- 5,7-dihydro-6H-dibenzrb~dlazepin-6-one A solution of 5-(N-Boc-amino)-5 ,7-dihydro-6H-dibenzb,d]azepin-6-one (0.2 g, 0.617 mmol) (Example 7-E) in DMF was treated with CSIC0 3 (0.3 g& 0.925 mmol) and warmed to 60"C. To the reaction mixture was added l-chloro-3,3dimethyl-2-butanone (0.096 ml, 0.74 mmol) (Aldrich) and stirring continued for WO 98/28268 PCT/US97t22986 303-- 17 h. After cooling to 23 the mixture was diluted with CH,CI,, washed with several portions of brine and dried over Na,S0 4 The title compound was isolated as a colorless solid.
C,
5
H
30
N
2 0 4 (MW 422.522); mass spectroscopy 423 Step B Synthesis of 5 -Amino- 7-3 .3 -dimethy I-2-butanonyt)- 5.7dihvdro-6H-dibenzrb~dlazepin-6-one Hydrochloride The compound isolated in Part A was deprotected in dioxane saturated with gaseous HCL The title compound was isolated as a colorless solid after evaporation and vacuum drying.
Example 7-1 Synthesis of L-Alaninyl-5-amino-7-methyl-5,7-dihydro- 6H-dibenzlb,dI azepin-6-one Hydrochloride Step A: Following General Procedure D and using N-t-Boc-L-alanine and 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, N-t-Boc-L-alaninyl- 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,dlazepin-6-one was prepared.
Step2 Following General Procedure 8-N and using the N-t-Boc-L- -amino- 7-methyl -5,7-dihydro-6H-dibenz[b,d]azepin-6-one, the title compound was prepared. Other substituted N-t-Boc-L-alaninyl-5-amino-7methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-ones can also be prepared by this procedure.
Example 74J Synthesis of L-Valinyl-5-amino-7-methyl-5,7-dihvdro- 6H-dibenzlb,dI azepin-6-one Hydrochloride Step A: Following General Procedure D and using N-t-Boc-L-valine and ,7-dihydro-6H-dibenz[b,dlazepin-6-one, ,7-dihydro-6H-dibenz[b,d]azepin-6-one was prepared.
WO 98/28268 WO 9828268PCTIUS97/22986 304 Step2 B: Following General Procedure 8-N and using the N-t-Boc-L-valinyl- 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, the title compound was prepared. Other substituted N-t-Boc-L-valinyl-5 -amino-7-methyl-5 ,7dihydro-6H-dibenz[b,dlazepin-6-ones can also be prepared by this procedure.
Example 7-K Synthesis of 5-Amino-7-phenbutyl-5,7-dihydro-6H-dibenzb,dj azepin-6-one Following General Procedure 7-A and using 5,7-dihydro-6Hdibenz[b,djazepin-6-one (prepared as described in Brown, et. al., Tetrahedron Letters, No. 8, 667-670, (1971) and references cited therein) and 1-chloro-4phenylbutane (Aldrich), the title compound was prepared.
Example 7-L Synthesis of 5-Amino-7-cyclopropymethyl-5,7-dihydro- 6H-dibenz[b,dJ azepin-6-one Following General Procedure 7-A and using 5,7-dihydro-6Hdibenz[b,djazepin-6-one (prepared as described in Brown, et. al., Tetrahedron Letters, No. 8, 667-670, (1971) and references cited therein) and (bromomethyl)cyclopropane (Aldrich), the title compound was prepared.
Example 7-M Synthesis of 5-Amino-7-(2 '-trifluoroethyl)-5,7-dihydro- 611-dibenz[b,dJ azepin-6-one Following General Procedure 7-A and using 5,7-dihydro-6Hdibenz[b,djazepin-6-one (prepared as described in Brown, et. al., Tetrahedron Letters, No. 8, 667-670, (1971) and references cited therein) and I -bromo-2,2,2trifluoroethane (Aldrich), the title compound was prepared.
WO 98/28268 PCTIU~S97298 305 Example 7-N Synthesis of 5-Amino-7-cyclohexyl-5,7-dihydro- 6H-dibenz[b,d]azepin-6-one Following General Procedure 7-A and using 5,7-dihydro-6Hdibenz[b,d]azepin-6-one (prepared as described in Brown, et. al., Tetrahedron Letters, No. 8, 667-670, (1971) and references cited therein) and bromocyclohexane (Aldrich), the title compound was prepared.
Example Synthesis of 5-(L-Alaninyl)amino-9-fluoro-7-methyl- 5,7-dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride Step 1: 2-Bromo-5-fluorotoluene was stirred in THF at -78C. s-BuLi (1.05 eq., 1.3 M in cyclohexane) was slowly added and the mixture was stirred for minutes. Trimethylborate (1.5 eq) was added and the mixture was allowed to warm to ambient temperature. After stirring for 1 hour, pinacol (2 eq.) was added. The mixture was stirred for 16 hours then was concentrated under reduced pressure. The resulting residue was slurried in CH,C1, and filtered through Celite. The filtrate was concentrated to yield an oil which was purified by chromatography on deactivated silica gel (Et 3 N) to yield the arylboronate ester.
Step 2: 2-Bromoaniline (1 eq.) and di-t-butyl-dicarbonate (1.1 eq.) were stirred at 80 0 C for 20 hours. The resulting mixture was allowed to cool and was directly distilled using house vacuum to provide N-t-Boc-2-bromoaniline.
Step 3: N-t-Boc-2-bromoaniline (Step 2, 1 the arylboronate ester (Step 1, 1.1 K,C0 3 (1.1 eq.) and tetrakis(triphenylphosphine)palladium(0) (0.02 eq) were stirred in 20% water/dioxane under nitrogen. The solution was heated at reflux for 10 hours. The mixture was allowed to cool then was concentrated.
The resulting residue was partitioned between water and chloroform. The WO 98/28268 PCTIUS97/22986 306 organic portion was dried and concentrated to yield an oil which was purified by silica gel chromatography using 1:1 CH,Cl,/hexanes.
Step 4: Following General Procedure 7-B and using the substituted biphenyl from step 3, the 9-fluoro-5,7-dihydro-6H-dibenz[b,d]azepin-6-one was prepared.
Step 5: 9-Fluoro-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1 eq., Step 4), cesium carbonate (1.1 eq., Aldrich) and methyl iodide (1.1 eq., Aldrich) were stirred in dry DMF at ambient temperature for 16 hours. The mixture was concentrated under reduced pressure to provide a residue which was partitioned between EtOAc and water. The organic portion was dried and concentrated to yield an oil which was purified by silica gel chromatography to 9-fluoro-7methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one.
Step 6: Following General Procedure 7-A, Step B and 9-fluoro-7-methyl- 5,7-dihydro-6H-dibenz[b,d]azepin-6-one from Step 5, 5-amino-9-fluoro-7methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one was prepared.
Step 7: Following the procedure of Example 7-I and using 5-amino-9fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one from Step 6, the title compound was prepared.
Example 7-P Synthesis of 5-(L-Alaninyl)amino-13-fluoro-7-methyl- 5,7-dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride Following the procedure of Example 7-0 and using 2-bromo-4-fluoroaniline (Step 2, Lancaster) and o-tolylboronic acid (Step 3, Aldrich), the title compound was prepared.
WO 98/8268 PCTIIUS97/22986 -307 Example 7-Q Synthesis of 1-fluoro-7-methyl- 5,7-dihydro-6H-dibenzlb,dI azepin-6-one Hydrochloride Following the procedure of Example 7-0 and using 2-bromo-4fluorotoluene (Step the title compound was prepared.
Example 7-R Synthesis of 5-(L-Alanyl)-amino-7-cyclopropylmethyl- 5,7-dihydro-6H-dibenzjb,dj azepin-6-one Hydrochloride Following the procedure of Example 7-1 and using 5-amino-7- ,7-dihydro-6H-dibenzb,d]azepin-6-one (Example the title compound was prepared.
Example 7-S Synthesis of 5-(L-Alaninyl)amino-7-phenbutyl- 5,7-dihydro-6H-dibenzlb,dJ azepin-6-one Hydrochloride Following the procedure of Example 7-1 and using 5-amino-7-phenbutyl- 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example the title compound was prepared.
Example 7-T Synthesis of 5-(L-Valinyl)amino-7-cyclopropylmethyl- 5,7-dihydro-6H-dibenzlb,dJ azepin-6-one Hydrochloride Following the procedure of Example 7-4 and using 5-amino-7- ,7-dihydro-6H-dibenz~b,d]azepin-6-one (Example the title compound was prepared.
Example 7-U Synthesis of 5-(L-Valinyl)amino-7-phenbutyl- 5,7-dihydro-6H-dibenzlb,dj azepin-6-one Hydrochloride WO 98/28268 PCT1US97/22986 308 Following the procedure of Example 74J and'using 5 -amino- 7-phenbutyl- 5,7-dihydro-6H-dibenz~b,d]azepin-6-one (Example the title compound was prepared.
Example 7-V Synthesis of 5-(L-Valinyl)amino-7-hexyl-5,7-dihydro- 6H-dibenz[b,djazepin-6-one Hydrochloride Sten2 Following General Procedure 7-A and using 5,7-dihydro-6Hdibenz[b,djazepin-6-one (prepared as described in Brown, et. al., Tetrahedron Letters, No. 8, 667-670, (1971) and references cited therein) and 1-bromohexane (Aldrich), 5-amino-7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one was prepared.
Step B: Following the procedure of Example 74J and using 5-amino-7hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, the title compound was prepared.
Example 7-W Synthesis of 5-(L-Valinyl)amino-1O-fluoro-7-methyl- 5,7-dihydro-6H-dibenzlb,dJ azepin-6-one Hydrochloride Following the procedure of Example 74J and using 5 -amino- I 0-fluoro- 7methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (as prepared in Examte77%~ the title compound was prepared.
Example 7-X Synthesis of 13-fluoro-7-methyl- 5,7-dihydro-6H-dibenz~b,dazepin-6-one Hydrochloride Following the procedure of Example 7-4 and using the 5-amino-13-fluoro-7methyl-5,7-dihydro-6H-dibenzb,d]azepin-6-one (as prepared in Example 7-P), the title compound was prepared.
WO 98/28268 PCT[US97/22986 309- Example 7-Y Synthesis of 5-(L-Valinyl)amino-13-fluoro-7-methyl- 5,7-dihydro-6H-dibenzlb,dl azepin-6-one Hydrochloride Following the procedure of Example 74J and using the 5-amino-9-fluoro-7- .methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (as prepared in Example the title compound was prepared.
Example 7-Z Synthesis of (5-Amino-7-methyl-1 ,2,3,4,5,7-hexahydro- 6H-dicyclohexyljb,dj azepin-6-one The 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-A) was dissolved in a 1:1 mixture of EtOAc/HOAc.
5% Rh/C was added and the mixture was stirred at 60*C under 60 psi of hydrogen. After 3 days, the mixture was filtered and the filtrate was concentrated to provide an oil which was purified by SCX-cation exchange chromatography to yield the title compound..
Example 7-AA Synthesis of S-(S)-Amino-7-methyl-5,7-dihydro- 6H-dibenzlb,djazepin-6-one Hydrochloride Following General Procedure 7-C using racemnic 5-amino-7-methyl-5,7dihydro-6H-dibenz[b,d]azepin-6-one (1.0 eq.) and di-p-toluoyl-D-tartaric acid monohydrate (1.0 eq.) in methanol, the title compound was prepared as a solid.
The product was collected by filtration. Enantiomeric excess was determined by chiral HPLC.
Desired enantiomer 1: retention time of 9.97 minutes.
Undesired enantiomer 2: retention time of 8.62 minutes.
NMR data was as follows: 'H-nmr (CDCl 3 8 9.39 2H), 7.75-7.42 (in, 4.80 IH), 3.-30 (s.
3H).
WO 98/28268 PCT1US97122986 310--
C,
5
HJ
5 CIN,O (MW 274.75); mass spectroscopy 239.1.
Anal Calcd for C, 5
H,
5 C1N,0 3 C, 65.57; H, 5.50; N, 10.20; Found: C, 65.51, H, 5.61; N, 10.01.
Example 7-1 Synthesis of 5-(S)-[N'-(3,5-Difluorophenylacetyl)-L-alaninylj amino- 7-methyl-5,7-dihydro-6H-dibenz~b,dj azepin-6-one Following General Procedure D above using alanine (Example B) and S-amino-7-methyl-5,7-dihydro-6H-dibenzb,d]azepin-6one hydrochloride (Example the title compound was prepared as a colorless solid. The diastereomers were purified by HPLC (Bulk OD-25) using EtOH in heptane as eluent and a flow rate of 1.5 mI/mmn.
Isomer 1: retention time of 11.4 minutes.
NMR data was as follows: 'H-nmr (CDCl 3 8 7.62-7.33 (in, 8H), 6.79 (in, 2H), 6.71 (in,IH), 6.47 (m,IH1), 5.24 (d 11H), 4.70 3.48 2H), 3.34 3H), 1.42 3H).
Optical Rotation: [a]1 2 0 =-125 589 nm (c 1, MeOH).
C
26 H,1 3
FN
3 0 3 (MW 463.49); mass spectroscopy 463.
Anal. Calcd for C, 6
H
23
F.,N
3 0 3 C, 67.38 H, 5.00 N, 9.06. Found: C, 67.49 H, 5.06 N, 8.93.
Example 7-2 Synthesis of IN'-((S)-3,5-Difluorophenyl-a-hyd roxyacetyl)-L-alaninylljamino- 7-methyl-5,7-dihydro-6H-dibenz [b,dI azepin-6-one and 5-(S)-IN'-((R)-3,5-Difluorophenyl-cx-hydroxyacetyl)-L-alaninylj amino- 7-methyl-5,7-dihydro-6H-dibenzfb,dj azepin-6-one Following General Procedure D above using 3,5-difluoromandelic acid and [L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example the title compound was prepared as a colorless solid. The diastereomers were purified by flash chromatography using 98:2 CHCl 3 /MeOH.
WO 98/28268 PCT/US97/22986 311 Isomer 1: NMR data was as follows: 'H-nmr (CDC1 3 6 =7.67 IH), 7.60-7.28 (in, 8H), 7.15 lH), 6.98 (mn, 2H), 6.74 5.21 4.94 4.61 4.56 (in, 1H), 3.34 3H), 1.42 3H).
Optical Rotation: [a] 20 =-121 589 nrn (c 1, MeOH).
C,2 6 H 3
F,N
3 0 4 (MW 479.488); mass spectroscopy 479.
Anal. Calcd for C,- 6 H 2 3
F.,N
3
O
4 C, 65.13 H, 4.83 N, 8.76. Found: C, 65.42 H, 4.73 N, 8.65.
Isomer 2: NMR data was as follows: 'H-nmr (CDC1 3 8 7.78 11H), 7.66 1H), 7.54-7.28 (in, 8H), 6.89 (in, 2H), 6.71 (in, 2H), 5.22 (d 1H), 4.92 4.01 (in, 11-), 3.37 3H), 1.39 3H).
Optical Rotation: 20 =-146 589 run (c 1, MeOH).
C,-
6 H 2 3
F,N
3 0 4 (MW 479.488); mass spectroscopy 479.
Anal. Calcd for C,- 6
H
23 F2N 3 0 4 C, 65.13 H, 4.83 N, 8.76. Found: C, 65.18, 4.82, 8.65.
Example 7-3 Synthesis of 5-(S)-IN'-(3,5-Difluorophenyl-cv-ketoacetyl)-L-alaninylI amino- 7-methyl-5,7-dihydro-6H-dibenzlb,dI azepin-6-one Following the Jones oxidation procedure (Fieser and Fieser, Reagents for Organic Synthesis, Vol. 1, p. 142) using 5-(S)-[((S/R)-3,5-difluorophenyl-a- ,7-dihydro-6H-dibenz[b,d]azepin-6one (Example the title compound was prepared as a colorless solid.
NMR data was as follows: 'H-ninr (CDCl 3 6 =7.92 (mn, 2H), 7.61-7.35 (mn, 8H), 7.08 (in, 5.31 4.74 3.38 3H), 1.56 3H).
C-
6 H.jFN 3 0 4 (MW 477.472); mass spectroscopy 477.
WO 98/28268 PCTIUS97/22986 312 Anal. Calcd for C, 6
H
2
,F,N
3 0; C, 65.4 4 ,44 N, 8.80. Found: C, 65.66 H, 4.71 N, 8.54.
Example 7-4 Synthesis of 5-(S)-[N'-(3,5-difluorophenylacetyl)-L-valinylI amnino- 7-methyI-5,7-dihydro-6H-dibenz~b,dj azepin-6-one Following General Procedure D above using 3,5-difluorophenylacetic acid and 5-(S)-[L-valinyl]-amino-7-methyl-5 ,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example the title compound was prepared as a colorless solid. The product was purified by flash chromatography using 98:2 CHC1 3 /MeOH.
NMR data was as follows: 'H-nmr (CDCl 3 6 7.54-7.25 (in, 8H), 6.74 (in, 2H), 6.74 (in, 2H), 6.70 (in, 1H), 6.49 1H), 5.26 (d,111), 4.49 (mn,H1), 3.43 2H), 3.35 3H), 2.06 (in, 1H), 0.91 (in, 6H).
Optical Rotation: [U] 2 0 144 589 im (c 1, MeOH).
C
2 8
H
27
F,N
3 0 3 (MW 491.543); mass spectroscopy 490.9 Anal. Calcd for C,,H 2 7
FN
3
O
3 C, 68.42 H, 5.54 N, 8.55. Found: C, 68.51 H, 5.82, N, 8.61.
Example Synthesis of amino- 7-methyl-5,7-dihydro-6H-dibenzjb,djazepin-6-one Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood) and [L-ter-leucinyl]-amino-7-nethyl-5 ,7-dihydro-6Hdibenz~b,d]azepin-6-one hydrochloride (Example the title compound was prepared as a colorless solid. The product was purified by flash chromatography using 98:2 CHCl 3 /MeOH.
NMR data was as follows: 'H-nmr (CDCI 3 8 7.58-7.36 (in, 9H), 6 .80 (in, 2H), 6.72 (in,1H). 6.25 111), 5.27 4.52 3.53 2H), 3.35 3H), 0.97 (in, 9H).
WO 98/28268 PCTIUS97/22986 313 Optical Rotation: [a]2 0 -137@ 589 nni (c MeOH).
C,
9
H.,
9
FN
3 0 4 (MW =505.57); mass spectroscopy 504.9 Anal. Calcd for C, 8
H,
7
F,N
3 0 4 C, 66.52 H, 5.92 N, 8.02. Found: C, 66.39 H, 5.76, N, 7.79.
Example 7-6 Synthesis of 5-(S)-[N'-((S)-3,5-Difluorophenyl-e-.hydroxyacetyl)-L-valinylI amino- 7-methyl-5,7-dihydro-6H-dibenzlb,dj azepin-6-one Following General Procedure D above using (S)-3,5-difluoromandelic acid and 5-(S)-[L-valinyl]-amino-7-methyl-5 ,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example the title compound was prepared as a colorless solid. The product was purified by flash chromatography using 98:2
CHCI
3 /MeOH.
NMR data was as follows: 'H-nmr (CDCl 3 8 7.78 1H), 7.53-7.25 (in, 8H), 6.86 (mn, 2H), 6.71 (in, 2H1), 5.22 1H), 4.76 114) 4.43 3.34 3H), 2.08 (in, 1H), 0.91 (in, 6H).
C,
8
H'
7
FN
3 0 4 (MW 507.542); mass spectroscopy 506.9 Anal. Calcd for C,gH, 7
F,N
3 0 4 C, 66.26 H, 5.32 N, 8.27. Found: C, 66.08 H, 5.62, N, 7.97.
Example 7-7 Synthesis of L-tert-Ieucinylj amino-7-methyl-5,7-dihydro- 6H-dibenz[b,dl azepin-6-one Following General Procedure D above using (S)-3,5-difluoromandelic acid and 5-(S)-[L-tert-leucinyl]-amino-7-methyl-5 ,7-dihydro-6H-dibenz[b,d]azepin-6one hydrochloride (Example the title compound was prepared as a colorless solid. The product was purified by flash chromatography using 98:2 CHCI,./MeOH.
NMR data was as follows: WO 98t28268 PTU9128 PCTfUS97/22986 314-- 'H-nmr (CDCl 3 8 7.67 IH), 7.54-7.25 (in, 8H), 6.83 (in, 2H), 6.69 (in, 2H), 5.22 1H), 4.74 IH) 4.44 3.35 3H), 0.97 (in, 9H).
C
29
H.,
9
F
2
N
3 0 4 (MW 521.569); mass spectroscopy 520.9 Anal. Calcd for C, 9
H
29
FN
3 0 4 C, 66.78 H, 5.60 N, 8.06. Found: C, 66.56 H, 5.85, N, 7.83.
Example 7-8 Synthesis of N'-(3,5-difluorophenylacetyl)-L-alaninylI amino- 7-(methoxyacetyl)-5,7-dihydro-6H- dibenz[b,djazepin-6-one Following General Procedure D and using alanine (Example B) and 5-amnino-7-(methoxyacetyl)-5,7-dihydro-6Hdibenz[b,d]azepin-6-one hydrochloride (Example the title compound was prepared as a colorless solid. The product was purified by flash chromatography.
NMR data was as follows: 'H-nmr (CDCl 3 8 7.61-7.215 (mn, 8H), 6.76 (in, 2H), 6.68 (mn, 1H), 6.53 and 6.40 (two d, 1H), 5.32 1H), 4.71 (mn, lH) 4.37 (in, 2H), 3.69 3H), 1.49 and 1.39 (two d, 3H).
C 28
H.,
5
F
2
N
3 0 5 (MW 521.518); mass spectroscopy 522 Anal. Calcd for C 28
H
2 5
F
2
N
3 0 5 .1.5 inol H,O; C, 61.30 H, 4.55 N, 7.65.
Found: C, 61.30 H, 4.53, N, 7.68.
Example 7-9 Synthesis of [N'-(3,5-Difluorophenylacetyl)-L-alaninylI amino- 7-(methylcarboxylate)-5,7-dihydro-6H-dibenzb,d azepin-6-one Following General Procedure lI-A, Method B and using difluorophenylacetyl)-L-alaninyl]-ainino-7-(methoxyacetyl)-5,7-dihydro-6Hdibenz[b,d]azepin-6-one (Example the title compound was prepared as a colorless solid. The product was purified by flash chromatography.
C,-
7
H'
2 3
F.N
3 0 5 (MW 507.49); mass spectroscopy 508 WO 98/28268 PCT1US97/22986 315 Anal. Calcd for C2 7 H 2 3
F,N
3 0 5 .2 mol H,0; C, 59.66 H, 4.23 N, 7.72.
Found: C, 59.88 H, 4.29, N, 7.66.
Example 7- Synthesis of [N'-(3,5-difluorophenylacetyl)-L-alaninyl] amino- 7-(3,3-dimethyl-2-butanoyl)-5,7-dihydro- 6H-dibenztb,dj azepin-6-one Following General Procedure D and using alanine (Example B) and 5-amino-7-(3,3-dimethyl-2-butanoyl)-5,7-dihydro-6Hdibenz[b,d]azepin-6-one hydrochloride (Example the title compound was prepared as a colorless solid. The product was purified by flash chromatography.
NMR data was as follows: 'H-nmr (CDCl 3 8 7.57 (in, 3H), 7.41 (in, 5H), 7.14 (mn, 1H), 6.78 (in, 2H), 6.68 (in, lH), 6.44 and 6.26 (two d, 1H), 5.34(d, 1H), 4.68 (in, 1H) 4.59 (mn, 2H), 3.52 and 3.47 (two s, 2H), 1.52 and 1.42 (two d, 3H), 1.23 9H).
C
3
,H
3 1
FN
3 0 4 (MW 547.599); mass spectroscopy 548 Anal. Calcd for C 3
,H
3
,F
2
N
3 0 4 .0.5 inol H,0; C, 66.89 H, 5.59 N, 7.54.
Found: C, 66.52 H, 5.73, N, 7.18.
Example 7-11 Synthesis of [N'-(3,5-difluorophenylacetyl)-L-alaninylI amino- 7-(morpholinylacetyl)-5,7-dihydro-6H-dibenz[b,djazepin-6-one Following General Procedure D using ,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7-9) and inorpholine (Aldrich), the title compound was prepared as a colorless foam. The product was purified by flash chromatography.
NMR data was as follows: 'H-nmr (CDCl 3 5 7.57-7.37 (mn, 8H), 6.81-6.69 (in, 3H), 5.35 (mn, 1H), 4.73- 4.67 (mn, 2H), 4.17 (mn, 111), 3.66-3.26 (in, 10 1.46 and 1.40 (two d, 3H).
WO 98/28268 PCT/US97/22986 316--
C
31
H
30
F,N
4 0 5 (MW 576.592); mass spectroscopy 577 Anal. Calcd for C 31
H
30
F,N
4 0 5 .0.5 mol H2O; C, 63.57 H, 5.12 N. 9.56.
Found: C, 63.41 H, 5.51, N, 8.92.
Example 7-12 Synthesis of 5-(S)-(N'-((S)-(+)-2-Hydroxy-3-methylbutyryl)-L-alaninyl)amino- 7-methyl-5,7-dihydro-6H-dibenzlb,dI azepin-6-one Following General Procedure H using (S)-(+)-2-hydroxy-3-methylbutyric acid (Aldrich) and 5-S-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6Hdibenz[b,djazepin-6-one (Example the title compound was prepared as a white solid. The product was purified by silica gel chromatography using gradient elution of MeOH/CH,C1 2 (1:99 -3:97).
NMR data was as follows: 'H-nmr (CDCl 3 8 7.94 J =7.0 Hz, 1H), 7.55-7.22 (in, 9H), 5.25 (d, J 7.5 Hz, 111), 4.79-4.75 (in, 1H1), 3.83 J 3.1 Hz, 1H1), 3.78 (br s, IH), .3.32 3H), 2.08-2.01 (in, IH), 1.36 J =7.0 Hz, 3H1), 0.83 J 7.0 Hz, 3H), 0.76 J =6.5 Hz, 3H).
C,-
3
H-,
7
N
3 0 4 (MW 409.48); mass spectroscopy 410.4.
Anal Calcd for C 23 H 7
N
3 0 4 C, 67.46; H, 6.65; N, 10.26; Found: C, 67.59; H, 6.66; N, 10.34.
Example 7-13 Synthesis of 5-[N'-Cyclopenty-v-hydroxyacety)-L-valinyI amnino- 7-methyl-5,7-dihydro-6H-dibenz(b,dJ azepin-6-one Following General Procedure D above using cyclopentyl-a-hydroxyacetic acid (Example P) and [L-valinyl] -amino- 7-methyl-5 ,7-dihydro-6Hdibenz[b,d]azepin-6-one hydrochloride (Example the title compound was prepared as a colorless solid. The product was purified by flash chromatography using 98:2 CHCl 3 /MeOH.
C1, 7
H
33
N
3 0 4 (MW 463.5); mass spectroscopy 464.
WO W828268 PCT/US97122986 317 Anal. Calcd for C 27
H
33
N
3 0 4 C, 69.96 H, 7.18 N, 9.06. Found: C, 69.72 H, 6.99, N, 8.91.
Example 7-14 Synthesis of 5-(S)-(N'-((S)-3,3-dimethyl-2-hydroxybutyryl)-L-alaninyl)amino.
7-methyl-5,7-dihydro-6H-dibenz[b,dJ azepin-6-one and 5-(S)-(N'-((R)-3,3-dimethyl-2-hydroxybutyryl)-L-alaninyl)amino- 7-Inethyl-5,7-dihydro-611-dibenzlb,dj azepin-6-one Following General Procedure H using 2-hydroxy-3,3-dimethylbutyric acid (Aldrich) and 5 -(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6Hdibenz[b,d]azepin-6-one (Example the title compound was prepared as a white solid. The product was purified by silica gel chromatography using gradient elution of MeOH/CH 2 Cl, (1:99 -3:97).
NMR data for isomer 1 was as follows: 'H-nr (CDC1 3 5 7.90 J 6.6 Hz, 1H), 7.57-7.24 (in, 8H), 6.99 (d, J =7.5 Hz, IH), 5.24 J 6.5 Hz, IH), 4.83-4.76 (in, IH), 3.69 IH), 3.32 3H), 3.19 (br s, 1H), 1.39 J 7.0 Hz, 3H), 0.96 9H).
C
24
H,
9
N
3 0 4 (MW 423.51); mass spectroscopy (MHW) 424.1.
Anal Calcd for C 24
H,
9
N
3 0 4 (isomer C, 68.07; H, 6.90; N, 9.92; Found: C, 68.22, H, 7.04; N, 9.91.
NMR data for isomer 2 was as follows: 'H-rnr (CDCl 3 8 8.00-7.99 (in, 7.97-7.30 (in, 8H), 7.03-7.00 (in, 1H), 5.25 J 7.0 Hz, IH), 4.82-4.75 (in, 1H), 3.69 111), 3.33 3H), 2.66 (br s, IH), 1.48 J 7.0 Hz, 3H), 0.98 9H).
C,
4 H,qN 3 0 4 (MW 423.5 mass spectroscopy (MW) 424. 1.
Anal Calcd for C, 4
H,
9
N
3 0 4 (isomer C, 68.07; H, 6.90; N, 9.92; Found: C, 67.77, H, 7.08; N, 9.66.
WO 98/8268 PCT1US97/22986 318-- Example 7-15 Synthesis of amino- 7-methyl-5,7-dihydro-6H-dibenzlb,dj azepin-6-one Following General Procedure D above using cyclopentyl-ct-hydroxyacetic acid (Example P) and 5-(S)-[L-tert-Ieucinyl]-amino-7-methyl-5,7-dihydro-6Hdibenz[b,d]azepin-6-one hydrochloride (Example the title compound was prepared as a colorless solid. The product was purified by flash chromatography using 98:2 CHCI 3 /MeOH.
C
28
H
3 5
N
3 0 4 mass spectroscopy 478.
Anal. Calcd for C 2 H35 4 NO 6.3 H, 5.57 N, 11.06. Found: C, 66.33 H, 5.67, N, 10.89.
Example 7-16 Synthesis of -Cyclopentyl-oe-hydroxyacetyl)-L-alaninylI amino- 7-methyI-5,7-dihydro-6H-dibenzib,dj azepin-6-one Following General Procedure D above using cyclopentyl-ax-hydroxyacetic acid (Example P) and 5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6Hdibenz[b,d]azepin-6-one hydrochloride (Example the title compound was prepared as a colorless solid. The product was purified by flash chromatography using 99:1 CHCl 3 IMeOH.
NMR data was as follows: 'H-nmr (CDCl 3 8 7.78 (in, 2H), 7.62-7.28 (in, 8H), 7.08 and 6.99 (two d, 1H), 5.27 1H), 4.78 (in, 1H), 4.06 (mn, IH), 3.34 3H), 2.54 (mn, 2H), 2.29 (in, 1H), 1.76-1.48 (in, 6H)1.43 3H).
C
25
H,-
9
N
3 0 4 .(435.52); mass spectroscopy 436 Anal. Calcd for C2 5
H
29
N
3 0 4 C, 68.95 H, 6.71 N, 9.65. Found: C, 69.06 H, 6.89, N, 9.51.
WO 98/28268 PCT/US97/22986 319-- Example 7-17 Synthesis of 5-IN'-(3,5-Difluorophenylacetyl)-L-alaninylI amino- 5,7-dihydro-6H,7H-dibenzl b,dl azepin-6-one Following General Procedure D above using alanine (Example B) and 5-amino-5,7-dihydro-6H,7H-dibenz[b,d]azepin-6-one hydrochloride (prepared using the compound of Example 7-E, followed by Boc removal as in Example 7-B3, Step the title compound was prepared as a colorless solid. The product was purified by flash chromatography using 95:5 CHC1 3 /MeOH.
NMR data was as follows: 'H-nmr (DMSOd 6 8 8.86 (in, lH), 8.75 (in, 1H), 8.49 (mn, 1H), 7.78- 7.23 (mn, 8H), 7.09 (in, 1H), 7.03 (mn, 2H), 5.07 (in, 4.60 (in, iN), 3.55 (s, 2H), 1.32 3H).
C
25
H,
1
F,N
3 0 3 .(449.45); mass spectroscopy 450.
Anal. Calcd for C 25
H,
1
F-,N
3 0 3 C, 66.81 H, 4.71 N, 9.35. Found: C, 67.11 H, 4.84, N, 9.09.
Example 7-18 Synthesis of 5-[N'-(3,5-Difluorophenylacetyl)-L-alaninyI amino- 7-(2-methylpropyl)-5,7-dihydro-6H-dibenzlb,dI azepin-6-one Following General Procedure D above using alanine (Example B) and 5-amino-7-(2-inethylpropyl)-5,7-dihydro-6Hdibenzb,d]azepin-6-one hydrochloride (Example the title compound was prepared as a colorless solid. The product was purified by flash chromatography using 99:1 CHCl 3 /MeOH.
NMR data was as follows: 'H-rnr (CDCl 3 5 7.58-7.33 (in, 4H), 7.40 (in, 4H), 6.81 2H), 6.71 (in,1H), 6.34 and 6.27 (two d, IH), 5.22 (d 1H), 4.69 (in,IH), 4.27 3.52 2H), 3.33 (in, 1.52 and 1.42 (two d, 3H), 0.57 and 0.29 (two d, 3H).
C,
9
H,
9
FN
3 0 3 (MW =505.562); mass spectroscopy 505.
WO 98/28268 PCTIUS97/22986 320 Anal. Calcd for C, 9
H,
9
F,N
3 0 3 C, 68.89 H, 5.78 N, 8.31. Found: C, 69.01 H, 6.02 N, 8.3 3.
Example 7-19 Synthesis of 5-[N'-(2-Hydroxy-3-methylhutyryl)-L-valinylI amino- 7-methyl-5,7-dihydro-611-dibenz[b,dj azepin-6-one Following General Procedure D above using 2-hydroxy-3-methylbutyric acid (Aldrich) and [L-valinyl]-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,d]azepin-6-one hydrochloride (Example the title compound was prepared as a colorless solid. The product was purified by flash chromatography using 98:2 CHCl 3 /MeOH.
NMR data was as follows: 'H-nmr (CDCl 3 8 7.69-7.25 (in, 8H), 7.08 and 6.92 (two d, IH), 5.29 4.54 (mn, IR), 4.01 (mn, IH), 3.36 3H), 2.12 (mn, 2H), 0.99 (mn, 6H), 0.83 (in, 6H).
C,
5
H
3
,N
3 0 4 .(437.537); mass spectroscopy 438.
Anal. Calcd for C,- 5
H-
3
,N
3 0 4 C, 68.63 H, 7.14 N, 9.60. Found: C, 68.71 H, 6.99, N, 9.42.
Example 7-20 Synthesis of R)-2-Hydroxy-3,3-dimethylbutyryl)-L-valinylI amino- 7-methyl-5,7-dihydro-6H-dibenz[b,dj azepin-6-one and R)-2-Hydroxy-3,3-dimethylbutyryl)-L-valinylI amino- 7-methyl-5,7-dihydro-6H-dibenzjb,dj azepin-6-one Following General Procedure D above using 2-hydroxy-3,3-dimethylbutyric acid (Aldrich) and 5-(S)-[L-valinyl]-amino-7-methyl-5 ,7-dihydro-6Hdibenz[b,d]azepin-6-one hydrochloride (Example the title compound was prepared as a colorless solid. The diastereoiners were purified by flash chromatography using 99:1 CHCl3)/MeOH.
Isomer 1: NMR data was as follows: WO 98/28268PcTU9I28 PCTIUS97/22986 321 'H-nmr (CDCl 3 8 7.60-7.28 (in, 8H), 6.63 1H), 5.26 1H), 4.53 3.74 IH), 3.35 3H), 2.12 (in, 1H), 0.998 (in, C,2 6
H-
33
N
3 0 4 (MW 451); mass spectroscopy 452.
Anal. Calcd for C2 6
H-
33
N
3 0 4 0.5 mol H-O; C, 67.80 H, 7.16 N, 9.11.
Found: C, 68.32 H, 7.06 N, 8.91.
Isomer 2: NMR data was as follows: 'H-nmr (CDCl 3 8 7.59-7.28 (mn, 8H), 6.82 5.25 11H), 4.52(m,IH), 3.74 3.33 3H), 2.16 (in, 1H), 0.997 (in,
C,-
6
H
33
N
3 0 4 (MW 451); mass spectroscopy 452 Anal. Calcd for C 2 6
H-
3 3
N
3 0 4 C, 69.16 H, 7.37 N, 9.3 1. Found: C, 69.33 H, 7.49 N, 9.22.
Example 7-22 Synthesis of IN'-(4-Phenyl-furazan-3-yi) alaninyl) -amino- 7-methyl-5,7-dihydro-6H-dibenzlb,dlazepin-6-one Following General Procedure D and using N-(4-phenyl-furazan-3-yl)alanine (Example I) and 5-amino-7-methyl-5 ,7-dihydro-6H-dibenz[b,d~azepin-6-one (Example the title compound was prepared. The reaction was monitored by tic (Rf 0.75, 5% MeOH/CHC 3 and product was purified by chromatography (silica, CHCl 3 NMR data was as follows: 'H-nmr (CDCl 3 5 4.52 (in, 4.87 11-).
MW 453.50; mass spectroscopy 454.
Example 7-23 Synthesis of 5-{N'-(3,5-Difluorophenylacetyl)-L-alaninyl) amino-7-methyl- 1 ,2,3,4,5,7-hexahydro-6H-dicyclohexylf b,dJ azepin-6-one Following Procedure D and using N-(3 (Ex. B) and 5-amino-7-methyl- 1,2,3,4,5,7-hexahydro-6Hdicyclohexyl[b,d]azepin-6-one (Example the title compound was prepared.
WO 98/28268 PCTIUS97/22986 322 The reaction was monitored by tic (Rf 0.3, 4% MeOH/CHC1 3 and product was purified by chromatography (silica, 4% MeOH/CHCI 3 NMR data was as follows: 'H-nrnr (CDCI 3 8 3.54 2H); 1.36 (in, 3H).
MW =475.58; mass spectroscopy 476.
Example 7-24 Synthesis of 5-{N'-(3,5-Difluorophenylacetyl)-L-alaninyl) amino- 7 -phenbutyl-5,7-dihydro-6H-dibenzlb,djazepin6one Following General Procedure D and using alanine (Ex. B) and 5-amino-7-phenbutyl-5 ,7-dihydro-6H-dibenzb,d]azepin-6one (Example the title compound was prepared. The reaction was monitored by tlc (Rf =0.35, 3% MeOH-/CHCI 3 and product was purified by chromatography (silica, 3% MeOH/CHCl 3 NMR data was as follows: 'H-nmr (CDCl 3 6 4.68 (in, 1H); 6.32 (dd, IH).
MW 581.66; mass spectroscopy 582.
Example 7-25 Synthesis of 3 ,5-Difluorophenylacetyl)-L-alaninyl) amino-.
7 -cyclopropymethyl-5,7-dihydro-6H-dibenz[b,dJ azepin-6-one Following General Procedure D and using alanine (Ex. B) and 5-amino-7-cyclopropymethyl-5,7-dihydro-6Hdibenz[b,d]azepin-6-one (Example the title compound was prepared. The reaction was monitored by tic (Rf 0.30, 5% MeOH/CHCI 3 and product was purified by, chromatography (silica, 3% MeOH/CHCl 3 NMR data was as follows: 'H-nmnr (CDCI 3 6 4.07 (in, lH); 4.70 (in, 1H); 5.24. IlH).
MW 503.55; mass spectroscopy 504.
WO 98/28268 PCT/US97/22986 323 Example 7-26 Synthesis of 5-{N'-(3,5-Difluorophenylacetyl)-L-alaninyl) amino- 7-(2 '-trifluoroethyl)-5,7-dihydro- 6H-dibenzlb,dl azepin-6-one Following General Procedure D and using alanine (Ex. B) and 5 -amino- -trifluoroethyl)-5,7-dihydro-6Hdibenz[b,d]azepin-6-one (Example the title compound was prepared. The reaction was monitored by tlc (Rf 0.15, 5% MeOl-/CHCl 3 and product was purified by chromatography (silica, 5% MeOH/CHC 3 NMR data was as follows: 'H-nmr (CDCl 3 5 4.07 (in, I1H); 4.69 (mn, IRH); 5.02 (in, I 5.3 7 (d, I H).
MW 531.48; mass spectroscopy 530.
Example 7-27 Synthesis of 5-{N'-(3,5-Difluorophenylacetyl)-L-alaninyl) amino- 7-cyclohexyI-5,7-dihydro-6H-dibenz~b,dIazepin-6-one Following General Procedure D and using alanine (Ex. B) and 5 -amino- 7-cyclohexyl- 5,7-dihydro-6H-dibenz[b,d] azepin-6one (Example the title compound was prepared. The reaction was monitored by tic (Rf 0.35, 5% MeOH/CHC 3 and product was purified by.
chromatography (silica, 5% MeOI-ICHCl 3 NMR data was as follows:.
'H-nmr (CDC1 3 86 1.43 (dd, 3H); 3.94 (in, I1H); 4.68 (in, I 5.18 (d, I1H).
MW 531.60); mass spectroscopy 533.
Example 7-28 Synthesis of IN'- I(S)-3,5-Difluoromandelyl]-L-alaninyl) amino- 9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[ b,dJ azepin-6-one WO 98t28268 PCTIUS97/22986 324 Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-alaninyl)-amino-9-fluoro-7-methyl-5, 7-dihydro-6Hdibenz[b,d]azepin-6-one hydrochloride (Example the title compound was prepared. The reaction was monitored by tic (Rf 10% MeOH/CHC 3 and product was purified by chromatography (silica, 2.5% MeOHICHCl 3 NMR data was as follows: 'H-rnr (CDCl 3 8 3.36 3H1); 4.67 (in, 1H); 5.05 1H); 5.21 (in, I1H).
MW 497.47; mass spectroscopy 498.
Example 7-29 Synthesis of i(S)-3,5-Difluoromandelyll -L-alaninyl} -amino- 13-fluoro-7-methyl-5,7-dihydro-6H-dibenzb,dI azepin-6-one Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-alaninyl)-amino- 13-fluoro-7-methyl-5,7-dihydro-6Hdibenz[b,djazepin-6-one hydrochloride (Example the title compound was prepared. The reaction was monitored by tic (Rf 10% MeOH/CHC 3 and product was purified by 2.5% chromatography (silica, MeOH/CHCl 3 NMR data was as follows: 'H-nmr (CDCl 3 6 1.45 (dd, 3H); 3.31 3H).
MW 497.47; mass spectroscopy 498.
Example 7-30 Synthesis of (N'-[(S)-3,5-DifluoromandelyJ -L-alaninyl) amino- 1 -fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,dI azepin-6-one Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-alaninyl)-amino-1I0-fluoro-7-methyl-5 ,7-dihydro-6Hdibenzb,d]azepin-6-one hydrochloride (Example the title compound was prepared. The reaction was monitored by tic (RI' 0.4, 10% MeOH/CHC 3 and product was purified by chromatography (silica, 2.5% MeOHICHC 3 NMR data was as follows: WO 98/28268 PCTIUS97/22986 325 'H1-nmr (CDCI 3 6 1.44 (dd, 3H); 3.35 3H).
MW 497.47; mass spectroscopy 498.
Example 7-31 Synthesis of IN'- I(S)-3,5-Difluoromandelylj-L-alaninyl) amnino- 7-cyclopropylmethyl-5,7-dihydro-6H-dibcnzb,dj azepin-6-one Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-alaninyl)-amino-7-cyclopropylmethyl-5,7-dihydro-6Hdibenz~b,d]azepin-6-one hydrochloride (Example the title compound was prepared. The product was purified by chromatography (silica, MeOH/CHC 3 NMR data was as follows: 'H-nnir (CDCI 3 6 1.48 (dd, 3H); 3.45 (in, IH).
MW 519.55; mass spectroscopy 520.
Example 7-32 Synthesis -of I(S)-3,5-Difluoromandelyll-L-alaninyl) amino- 7-phenbutyl-5,7-dihydro-6H-dibenz[b,djazepin-6-one Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-alaninyl)-amino-7-phenbutyl-5,7-dihydro-6Hdibenzb,d]azepin-6-one hydrochloride (Example the title compound was prepared. The product was purified by chromatography (silica, 1-2% MeOHICHCl 3 NMR data was as follows: 'H-nmr (CDCI 3 6 1.48 (dd, 3H); 5.04 114).
MW 597.66; mass spectroscopy 599.
Example 7-33 Synthesis of {N'-IS)-3,5-Difluoromandelyll -L-valinyl) amino- 7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,dj azepin-6-one WO 98/28268 PCT/US97/22986 326 Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-valinyl)-amino-7-cyclopropylmethyl-5 ,7-dihydro-6Hdibenz[b,d]azepin-6-one hydrochloride (Example the title compound was prepared. The reaction was monitored by tic (Rf 2.5% MeOH/CHC 3 and product was purified by chromatography (silica, 2.5% MeOH/CHCl 3 NMR data was as follows: 'H-nmr (CDCI 3 5 3.42 (in, 1H); 4.07 (in, 114); 5.03 IlH).
Example 7-34 Synthesis of [(S)-3,5-DifluoromnandelyII -L-vaijnyI) amino- 7-phenbutyI-5,7-dihydro-6H-dibenz~b,diazepin-6-one Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-valinyl)-amino-7-phenbutyl-5,7-dihydro-6Hdibenz[b,d]azepin-6-one hydrochloride (Example the title compound was prepared. The product was purified by chromatography (silica, 1-2% MeOHICHC 3 NMR data was as follows: 'H-nmr (CDCI 3 8 3.54 (mn, IH); 4.35 (in, 1H); 5.03 111).
MW 625.71; mass spectroscopy 625.
Example 7-35 Synthesis of 5-{N'+[S)-3,5-Difluoromnandelylj -L-valinyl) amino- 7-hexyl-5,7-dihydro-6H-dibenz[b,djazepin-6-one Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-valinyl)-amino-7-hexyl-5,7-dihydro-6H-dibenz[b.d]azepin- 6-one hydrochloride (Example the title compound was prepared. The product was purified by chromatography (silica, 5% MeOH/CHCI 3 NMR data was as follows: 'H-nmr (DMSO-d 6 86 4.25 (mn, 1H); 4.52 (mn, 1H); 5.05 5.24 (2 doublets, I H).
MW 577.67; mass spectroscopy 578.
WO 98/28268 PCTUS97/22986 327 Example 7-36 Synthesis of IN'- i(S)-3,5-DifluoromandelyIJ -L-valinyI) amino- I O-fluoro-7-methyl-5,7-dihydro-6H-dibenzlb,dI azepin-6-one Following General Procedure D and using (S)-3,5-difluoromaridelic acid (Example L) and 5-(L-valinyl)-amino- 10-fluoro-7-methyl-5 ,7-dihydro-6Hdibenz[b,d]azepin-6-!one hydrochloride (Example the title compound was prepared. The product was purified by chromatography (silica, MeOH/CHC 3 Anal. Ca~c.: C, 71.02; H, 5.96; N, 6.72. Found: C, 71.10, H, 6.12, N, 6.63.
Example 7-37 Synthesis of (N'-IS)-3,5-DifluoromnandelyIJ -L-valinyl} amino- 13-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,djazepin-6-one Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-valinyl)-amino- 13 -fluoro-7-methyl-5 ,7-dihydro-6Hdibenz[b,d]azepin-6-one hydrochloride (Example the title compound was prepared. The product was purified by chromatography (silica, MeOH/CHC 3 Anal. Calc.: C, 71.02; H, 5.96; N, 6.72. Found: C, 71.10, H, 6.12, N, 6.63.
Example 7-38 Synthesis of 5- I(S)-3,5-Difluoromandelyll -L-valinyl) amino- 9-fluoro-7-methyl-5,7-dihydro-611-dibenz[b,dj azepin-6-one Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-valinyl)-amino-9-fluoro-7-methyl-5 ,7-dihydro-6Hdibenzb,d]azepin-6-one hydrochloride (Example the title compound was prepared. The product was purified by chromatography (silica, MeOHICHC 3 Anal. Caic.: C, 71.02; H, 5.96; N, 6.72. Found: C, 71.10, H, 6.12, N, 6.63.
WO 98/28268 PCT/US97/22986 328 8. Benzodiazepine Derivatives and Related Compounds GENERAL PROCEDURE 8-A N-1-Methylation of Benzodiazepines A solution of benzodiazepine (1 eq.) in DMF (0.1 M concentration) at 0 C was treated with potassium tert-butoxide (1.0 eq., 1.0 M solution in THF).
After stirring for 30 minutes at 0°C, iodomethane (1.3 eq.) was added and stirring continued for 25 minutes. The mixture was diluted with methylene chloride and washed with water and brine. The organic phase was dried over Na2SO 4 filtered, and concentrated. The crude product was then either purified by trituration with 1:1 ether/hexanes or chromatographed via HPLC using ethyl acetate/hexanes as the eluent.
GENERAL PROCEDURE 8-B Cbz Removal Procedure A flask was charged with the Cbz-protected 3-aminobenzodiazepine (1 eq.).
To this was added HBr (34 eq.; 30% solution in acetic acid). Within 20 minutes all of the starting material dissolves. The reaction was stirred for 5 hours at ambient temperature. Ether was added to the orange solution causing the HBr*amine salt to precipitate. The mixture was decanted. This process of adding ether and decanting was repeated thrice in an effort to remove acetic acid and benzyl bromide. Toluene was added and the mixture concentrated in vacuo.
This step was also repeated. The HBr salt was partitioned between ethyl acetate and 1 M KCO 3 The aqueous layer was back-extracted with ethyl acetate. The combined organics were washed with brine, dried over Na2SO 4 filtered, and concentrated.
GENERAL PROCEDURE 8-C Boc Removal Procedure A solution of Boc-protected amine (1 eq.) in methylene chloride (0.15 M concentration) was cooled to 0 0 C and treated with trifluoroacetic acid (30 eq.).
WO 98/28268 PCT/US97/22986 329 After 10 minutes at 0°C, the cooling bath was removed and stirring continued at ambient for 20 minutes to 1 hour. The mixture was concentrated in vacuo to remove excess trifluoroacetic acid. The residue was dissolved in methylene chloride and washed with saturated aqueous NaHCO 3 or 1 M KCO3 and brine.
The organic layer was dried over Na2SO 4 filtered, and concentrated.
GENERAL PROCEDURE 8-D Azide Transfer Reaction Using KHMDS The azido derivative was prepared using the procedure described in John W.
Butcher et al., Tet. Lett., 37, 6685-6688 (1996).
GENERAL PROCEDURE 8-E Azide Transfer Reaction Using LDA To a solution of diisopropylamine (1.1 eq.) in 1 mL of dry THF cooled to 78 0 C was added n-butyl lithium (1.6M in hexane) (1.1 eq.) dropwise maintaing the reaction temperature at -78 0 C. The reaction mixture was stirred for 30 min.
at -78 0 C and then the lactam (0.471 mM) was added dropwise as a solution in 1 mL of dry THF. The reaction mixture was stirred at -78 0 C for 30 min. and then a pre-cooled solution of trisyl azide (1.2 eq.) was added as a solution in 1 mL of dry THF. The reaction mixture was stirred at -78 0 C for 20 min. and then quenched with acetic acid (4.0 The reaction mixture was then stirred at 0 C for 2 hrs. The reaction was then poured into EtOAc and washed with water, sodium bicarbonate and brine, and then dried over sodium sulfate, filtered and concentrated. The residue was purified by LC 2000 chromatography.
GENERAL PROCEDURE 8-F Azido Group Reduction The azido group was reduced to the corresponding primary amine using the procedure described in John W. Butcher et al., Tet. Lett., 37, 6685-6688 (1996).
WO 98/28268 PCT/US97t22986 330 GENERAL PROCEDURE 8-G N-Alkylation of Amides or Lactams Using Sodium Hydride or Potassium tert-Butoxide To a slurry of sodium hydride or potassium tert-butoxide (1.1 eq) in 15 mL of dry DMF was added the appropriate amide (0.0042 moles) as a solution in mL of DMF. The alkyl iodide was then added and a thick slurry resulted. The reaction became less thick as time elapsed and when complete by TLC the reaction had become homogeneous. The reaction mixture was poured over ice and extracted into ethyl acetate. The organic layer was washed with water, followed by brine. The organic layer was then dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by HPLC (LC 2000), eluting with an ethyl acetate/hexane system.
GENERAL PROCEDURE 8-H N-Alkylation of Amides or Lactams Using KHMDS To the appropriate amide or lactam in THF cooled to -78°C was added KHMDS dropwise and the reaction mixture was stirred for 30 min. at -78 0
C.
The alkyl iodide was then added dropwise while maintaining the temperature at -70°C. The cooling bath was then removed and reaction was allowed to warm to room temperature and stirring was continued for 2 hours. The reaction mixture was then poured over ice and extracted into ethyl acetate. The organic extracts were washed with water, followed by brine. The organic layer was then dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by HPLC (LC 2000), eluting with an ethyl acetate/hexane system.
GENERAL PROCEDURE 8-I N-Alkylation of Amides or Lactams Using Cesium Carbonate To a solution of the amide or lactam in DMF was added cesium carbonate (1.05 eq) and an alkyl iodide (1.1 eq). The mixture was allowed to stir overnight at room temperature and then the reaction mixture was dilluted with WO 98/28268 PCT/US97/22986 331 ethyl acetate and washed with water, followed by brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by HPLC (LC 2000), eluting with an ethyl acetate/hexane system.
GENERAL PROCEDURE 8-J BOC Removal Procedure To an N-Boc protected compound was added CH,C12/TFA at room temperature. The reaction mixture was stirred at room temperature for 3 hours and then concentrated. The residue was extracted into dichloromethane and washed with water, saturated sodium bicarbonate, dried over NaSO 4 filtered and concentrated to give the free amine.
GENERAL PROCEDURE 8-K Azide Transfer Procedure This azide transfer procedure is a modification of the procedure described in Evans, D. Britton, T. Ellman, J. Dorow, R. L. J. Am. Chem. Soc.
1990, 112, 4011-4030. To a solution of the lactam substrate (1.0 eq.) in THF M) under N, at -78 OC was added a solution of KN(TMS)2 (1.1 eq. of M in Toluene, Aldrich) dropwise over a period of 2-10 minutes. A slight exotherm was often observed by an internal thermometer, and the resulting solution was stirred for 5-15 minutes, while re-cooling to -78 0 C. Then, trisyl azide (1.1-1.5 eq., CAS No. 36982-84-0, prepared as described by references in the Evans reference above) in THF either precooled to -78 0 C or at room temperature, was added via cannula over a period of 0.5-5 minutes.
Again, a slight exotherm was generally noted. The resulting solution was stirred for from 5-10 minutes, while re-cooling to -78 0 C. Then, AcOH (4.5-4.6 eq., glacial) was added, the cooling bath removed and the mixture allowed to warm to room temperature with stirring for 12-16 hours. The mixture was diluted with EtOAc, in a 2-5 volume multiple of the initial THF volume, and washed with dilute aq. NaHCO 3 0.1-1.0 M aq. HCI and brine The WO 98/28268 PCT/US97/22986 332 organic phase was then dried over MgSO 4 filtered, concentrated to provide the crude product.
GENERAL PROCEDURE 8-L Azide Reduction to an Amine A mixture of the azide in absolute EtOH (0.03-0.07 M) and 10% Pd/C by weight of the azide) was shaken in a Parr apparatus under H, (35-45 psi) at room temperature for 3-6 hours. The catalyst was removed by filtration through a plug of Celite, rinsing with absolute EtOH, and the filtrate concentrated to provide the crude amine product.
GENERAL PROCEDURE 8-M Amide Alkvlation Using Cesium Carbonate This procedure is a modification of the procedure described in Claremon, D.
et al, PCT Application: WO 96-US8400 960603. To a mixture of 2,4dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (CAS No. 49799-48-6) in DMF eq., 0.7 M) under N, at room temperature was added Cs,CO 3 (2.2 eq.) and the appropriate alkyl halide (2.2 The mixture was stirred at room temperature for 5.5-16 hours. The mixture was partitioned between EtOAc and sat. NaHCO 3 The aqueous layer was extracted with EtOAc (1-2x) and the combined EtOAc extracts were dried over Na2SO 4 filtered, and concentrated to provide the crude product.
GENERAL PROCEDURE 8-N BOC Removal Procedure A stream of anhydrous HCI gas was passed through a stirred solution of the N-t-Boc protected amino acid in 1,4-dioxane (0.03-0.09 chilled in a ice bath to -10°C under for 10-15 minutes. The solution was capped, the cooling bath removed, and the solution was allowed to warm to room temperature with stirring for 2-8 hours, monitoring by TLC for the consumption of starting material. The solution was concentrated (and in some instances dissolved in WO 98/28268 WO 98/28268 PCT/US97/22986 333 CHCl, then re-concentrated and placed in vacuum oven at 60-70 0 C to remove most of the residual dioxane) and used without further purification.
Example 8-A Synthesis of 3-Amino-1,3-dihydro-5-(1-piperidinyl)-2H-1,4-benzodiazepin-2-one Step A Preparation of 1.2-Dihvdro-3H-l-methvl-5-(1-piperidinvl)- 1,4-benzodiazepin-2-one A solution of phosphorous pentachloride (1.2 eq) in methylene chloride was added dropwise to a solution of 1-methyl-1,2,3,4-tetrahydro-3H-1,4- (Showell, G. Bourrain, Neduvelil, J. G.; Fletcher, S. Baker, Watt, A. Fletcher, A. Freedman, S. Kemp, J. Marshall, G. Patel, Smith, A. Matassa, V. G. J. Med. Chem.
1994, 37, 719.) in methylene chloride. The resultant yellowish-orange solution was stirred at ambient temperature for 2.5 hours; the solvent was removed in vacuo. The orange residue was redissolved in methylene chloride, cooled to 0 and treated with a solution of piperidine (2 eq) and triethylamine (2 eq) in methylene chloride. The cooling bath was removed and the reaction stirred for 18 hours. The reaction mixture was washed with saturated aqueous NaHCO 3 (back-extracted with methylene chloride) and brine. The organic phase was dried over NaSO 4 filtered, and concentrated. The residue was purified via HPLC eluting with a gradient of 4 to 10% methanol/methylene chloride affording the title intermediate as a yellow solid having a melting point of 103- 105 0
C.
CisH,,N 3 0 (MW 257.37); mass spectroscopy 257.
Anal. Calcd for C,,H,,N 3 0: C, 70.01; H, 7.44; N, 16.33. Found: C, 69.94; H, 7.58; N, 16.23.
Step B Preparation of 1,2-Dihvdro-3H-1-methvl-3-oximido-5-(1piperidinvl)- 1.4-benzodiazepin-2-one Potassium tert-butoxide (2.5 eq) was added in two portions to a -20 0
C
solution of 1,2-dihydro-3H-1 -methyl-5-(1 -piperidinyl)- 14-benzodiazepin-2-one WO 98/28268 PCTIUS97/22986 334 (1 eq) in toluene). After stirring at 201C for 20 min, isoamyl nitrite (1.2 eq.; Aldrich) was added to the red reaction mixture. The reaction was stirred at 0 C for 5 hours at which time the reaction was done by TLC. The cooling bath was removed and the reaction quenched with 0.5 M citric acid. After stirring for 10 minutes, diethyl ether was added. The suspension was stirred at ambient temperature overnight then filtered washing with ether. The resultant cream colored solid had a melting point of 197-200*C.
'H NMR data of the E/Z isomers was as follows: 'H NMR (300 MHz, CDCl 3 86 7.64 (1 H, bs), 7.48 (2H, d, J=7.4 Hz), 7.35-7.20 (6H, in), 6.75 bs), 3.8-3.2 (8H, in), 3.46 (3H, 3.42 (3H, s), 1.90-1.40 (12H, mn).
C,
5
H,
8
N
4 0 2 (MW 286.37); mass spectroscopy 286.
Step C Prenaration of 1.2-dihvdro-3H-l-methyl-3-[O- (ethylaminocarbonvl)oximidol-5-(1I-n2iperidinyl)- 1,4benzodiazepin-2-one A mixture of 1 ,2-dihydro-3H-1I-methyl-3-oximido-5-( 1-piperidinyl)- 1,4benzodiazepin-2-one (1 eq) in THF was treated with ethyl isocyanate (1.7 eq) and triethylamine (0.6 eq). The mixture was heated to 64'C for 4 hours. The mixture was concentrated and the residue purified by HPLC eluting with methanol/methylene chloride.
'H NMR data of the E/Z isomers was as follows: 'H NMR (300 MHz, CDC1 3 8 7.50 (2H, dd, J=8.4, 1.5 Hz), 7.35-7.22 (6H, mn), 6.42 (lH, bt), 6.20 (IH, bt), 3.7-3.4- (8H, in), 3.46 (3H, 3.44 (3H, 3.25 (4H, in), 1.9-1.4 (12H, in), 1.12 (3H, t, J=6.3 Hz), 1.10 (3H, t, J=6.3 Hz).
Cj 8
H,-
3
N
5 0 3 (MW 357.46); mass spectroscopy 357.
Step D Preparation of 3 -Amino-I 1,3 -dihydro-2H- I -methvl-5 1piperidinyl)- I .4-benzodiazepin-2-one The 1 ,2-dihydro-3H-1I-methyl-3-[O-(ethylaminocarbonyl)oxiinido]-5-(I piperidinyl)-l1,4-benzodiazepin-2-one (1 eq) was hydrogenated in methanol over WO 98/28268 PCT/US97/22986 335 palladium on carbon 15 eq) at 43 psi for 3.25 hours. The reaction was filtered through celite and concentrated in vacuo. The residue was taken up in methylene chloride and filtered a second time through celite. The filtrate was concentrated and the resultant foam was used immediately.
Example 8-B, Synthesis of 3-(L-Alaninyl)-amino-2,3-dihydro- 1-methyl-5-phenyl-1 H-i ,4-benzodiazepin-2-one Step A Preparation of -amino- 1.3-dihydro- I-methyl- 5 -phenyl 2H- 1 4-benzodiazepin-2-one. (I S)-7,7-dimethvl-2oxobicyclor2.2. I Iheptane- I -methanesulfonate The title intermediate was prepared according to Reider, P. Davis, P.; Hughes, D. Grabowski, E. J. J. J Org. Chem. 1987, 52, 955 using 3-amino- 1 ,3-dihydro-lI-methyl-5-phenyl-2H- 1,4-benzodiazepin-2-one (Bock M. G.; DiPardo, R. Evans, B. Rittle, K. Veber, D. Freidinger, R. M.; Hirshfield, Springer, J. P. J1 Org. Chem. 1987, 52, 3232.) as the starting material.
Step B Prevaration of 3 -[N'-(tert-Butylcarbamate)-L-alaninvflI-amino- 2.3-dihydro- I -methyl- 5 -1henyl- I H- I .4-benzodiazepin-2 -one 3-Amino- 1 ,3 -dihydro- 1 -methyl-5 -phenyl-2H- 1 ,4-benzodiazepin-2-one, (1 S)-7,7-dimethyl-2-oxobicyclo[2.2. 1 heptane-l1-methanesulfonate was free based by partitioning between methylene chloride and 1IM potassium carbonate. The free amine was then coupled with N-Boc-alanine following General Procedure
D.
CI1 4
H.,
8
N
4 0 4 (MW 436.56); mass spectroscopy 436.
Anal. Calc. for C, 4
H,
8
N
4 0 4 C. 66.03; H, 6.47; N, 12.84. Found: C, 65.79; H, 6.68; N, 12.80.
Step C Preparation of 3-(L-Alaninvl)-amino-2,3-dihvdro- I-methyl- 12henyl- I H- 1,4-benzodiaze]2in-2-one WO 98/28268 PTU9128 PCTfUS97/22986 336 Following General Procedure 8-C using 3-[N'-(tert-butylcarbamate)-Lalaninyl]-amino-2,3-dihydro-l1-methyl-5 -phenyl-l1H-i ,4-benzodiazepin-2-one, the title compound was prepared as a white foam.
Anal. Calc. for C 19
H
19
N
4 C, 69.2 1; H, 6.64; N, 15.37. Found: C, 70.11; H, 6.85; N, 15.01.
Example 8-C Synthesis of 3-(L-Alaninyl)-amino-7-chloro-2,3-dihydro- 1-methyl-5-phenyl-1H-1 ,4-benzodiazepin-2-one Step A Preparation of 3-(Benzyloxvcarbonvl)-amino-7-chloro-2,3dihvdro- I -methyl-5-phenyl- 1 H-i 1,-benzodiazeipin-2-one A solution of 3-(benzyioxycarbonyl)-amino-7-chloro-2,3-dihydro-5-phenyl- I H-i ,4-Benzodiazepin-2-one (1 eq; Neosystem) in DMF was cooled to 0 0 C and treated with potassium tert-butoxide (1 eq; I OM solution in THF). The resultant yellow solution was stirred at 0 0 C for 30 minutes then quenched with methyl iodide (1.3 eq). After stirring an addition 25 minutes the reaction was diluted with methylene chloride and washed with water and brine. The organic phase was dried over Na 2
SO
4 filtered, and concentrated. The residue was purified via HPLC chromatography eluting with a gradient of 20-+30% ethyl acetate/hexanes.
C-
4
H,
0 C1N 3 0 3 (MW 433.92); mass spectroscopy 433.
Anal. calcd for C, 4
H
20 C1N 3 0 3 C, 66.44; H, 4.65; N, 9.68. Found: C, 66.16; H, 4.50; N, 9.46.
Step B Prep~aration of 3-Amino-7-chloro-1I.3-dihydro-lI-methvl-5p2henyl-2H- 1 ,4-benzodiazepin-2-one Following General Procedure 8-B using 3-(benzyloxycarbonyl)-amino-7chloro-2,3-dihydro- 1-methyl-5-phenyl- 1H-i ,4-benzodiazepin-2-one, the title intermediate was prepared as a white foam which was used immediately in Step
C.
WO 98/28268 PCT1US97/22986 337 Step C Preparation of 3 4 '-tert-Butvlcarbamate)-L-alaninI I -amino- 7-chloro- 1.3-dihvdro-lI-methvl-5-phenvl-2H- 1.4benzodiazepin-2-one Following General Procedure D using N-Boc-L-alanine and 3-amino-7chloro- 1, 3-dihydro-l1-methyl-5-phenyl-2H-1I,4-benzodiazepin-2-one, the title intermediate was prepared as a white foam.
C,,H,
8 C1N 4 0 4 (MW 471.18); mass spectroscopy 471 Anal. calcd for C 24
H
28 C1N 4 0 4 C, 61.21; H, 5.78; N, 11.90. Found: C, 61.24; H, 5.59; N, 11.67.
Step D Preparation of 3-(L-Alaninvl)amino-7-chloro-1I.3-dihvdro- 1methyl-5-phenyl-2H- 1 .4-benzodiazepin-2-one Following General Procedure 8-C using -tert-butylcarbamate)-Lalaninyl]-amino-7-chloro- 1 ,3-dihydro- I -methyl-5-phenyl-2H- 1 ,4-benzodiazepin- 2-one, the title intermediate was prepared as a white foam. The crude material was used immediately.
Example 8-D Synthesis of 3-(L-Alaninyl)amino-7-bromo-2,3-dihydro- 1 -methyl-5-(2-fluorophenyl)-1H-1 ,4-benzodiazepin-2-one Step A Preparation of 3-(Benzyloxycarbonyl)-amino-7-bromo-2,3dihydro- 1 -methyl-5-(2-fluorophenyl)- 1 H-i ,4-benzodiazepin-2one Following General Procedure 8-A using 3-(benzyloxycarbonyl)-amino-7bromo-2.3-dihydro-5-(2-fluorophenyl)- IH-I ,4-benzodiazepin-2-one (Neosystem), the title intermediate was prepared as a white foam.
C.,
4
H
19 BrFN 3
O
3 (MW 496.36); mass spectroscopy 497.
Anal. calcd for C, 4
H
1 9 BrFN 3
O
3 C, 58.08; H, 3.86; N, 8.47. Found: C, 57.90; H, 4.15; N, 8.20.
Step B Preparation of 3 -Amino-7-bromo-1I.3-dihydro- i-methvl-5-(2fluorophenvl)-2H- 1 .4-benzodiazepin-2-one WO 98/28268 PCTfUS97/22986 338 Following General Procedure 8-B using 3 -(benzyloxycarbonyl)-amino-7bromo-2,3-dihydro-l1-methyl-5-(2-fluorophenyl)- 1H-i ,4-benzodiazepin-2-one, the title intermediate was prepared as a white foam which was used immediately in Step C.
Step C Preparation of 3-[rN'-(tert-Butvlcarbamate)-L-alaninylI -amino- 7-bromo- I .3-dihydro- 1 -methvl-5-(2-fluorophenvl)-2H-- 1,4benzodiazepin-2-one Following General Procedure D using N-Boc-L-alanine (Novo) and 3 amino-7-bromo- 1 ,3-dihydro- 1 -methyl-5-(2-fluorophenyl)-2H- 1 ,4-benzodiazepin- 2-one, the title intermediate was prepared as a white foam.
C,
4
H
2 6 BrFN 4
O
4 (MW 533.12); mass spectroscopy 533.2.
Anal. calcd for C,- 4
H
2 6 BrFN 4
O
4 C, 54.04; H, 4.91; N, 10.50. Found: C, 53.75; H, 4.92; N, 10.41.
Step D Preparation of 3-(L-Alaninyl)-amino-7-bromo-1I 3-dihydro- 1methyl-5-(2-fluorophenyl)-2H- 1 .4-benzodiazepin-2-one Following General Procedure 8-C using 3-IIN'-(tert-butylcarbamate)-Lalaninylj-amino-7-bromo-1I,3-dihydro-lI-methyl-5-(2-fluorophenyl)-2H- 1,4benzodiazepin-2-one, the title intermediate was prepared as a white foam. The crude -material was used immediately.
Example 8-E Synthesis of 3-(N'-Methyl-L-alaninyl)-amino-2,3-dihydro- 1 -methyl-5-phenyl-1H- 1,4-benzodiazepin-2-one Step A Preparation of 3-[N'-(ert-Butvlcarbamate)-N'-methvl-Lalaninvll-amino-2.3-dihvdro-l1-methvl-5-Rhenyl- 1H-i .4benzodiazelpin-2-one Following General Procedure D and using -amino- 1,3 -dihydro-lImethyl-5-phenyl-2H- 1,4-benzodiazepin-2-one (Example 8-B3) and N-tert-Boc-Nmethyl-alanine (Sigma), the title intermediate was obtained as a white solid.
1
H
30
N
4 0 4 (MW 450.2); mass spectroscopy 451.2.
WO 98/28268 PTU9128 PCT/US97/22986 339 Anal. calcd. for C,- 5
H
30
N
4 0 4 C, 66.65; H, 6.71; N, 12.44. Found: C, 66.66; H, 6.89; N, 12.21.
Step A Preparation of 3 -Methyl-L-alaninvl)-amino-2,3-dihydro- Imethyl-5-phenyl- 1 H-i .4-benzodiazeipin-2-one Following General Procedure 8-C and using 3-[N'-(tert-butyicarbamate)-N'methyl-L-alaninyl]-amino-2,3-dihydro-l1-methyl-5-phenyl- 1H-I ,4-benzodiazepin- 2-one, the title intermediate was prepared as a white foam.
C-,
0
H,
2
N
4 0, (MW =350.46); mass spectroscopy 351.4.
Anal. calcd for C 20
H
22
N
4 01-: C, 68.55; H, 6.33; N, 15.99. Found, C, 68.36; H, 6.20; N, 15.79.
Example 8-F Synthesis of 3-(L-Alaninyl)amino-7-chloro-2,3-dihydro- 1-methyl-5-(2-chlorophenyl)-l1H-i ,4-benzodiazepin-2-one Step A Preparation of 3-(BenZyloxvcarbonyl)-amino-7-chloro-2,3dihydro- 1 -methyl-5-(2-chlorophenl)- I H- 1,4-benzodiazepin-2one Following General Procedure 8-A using 3-(benzyloxycarbonyl)-amino-7chloro-2,3-dihydro-5-(2-chlorophenyl)- IH-i ,4-benzodiazepin-2-one (Neosystemn), the title intermediate was prepared as a white solid having a melting point of 232-233 0
C.
C
24
H
19 C1 2
N
3 0 3 (MW 468.36); mass spectroscopy 468.
'H NMR (300 MHz, CDCI 3 6 7.67 (1IH, in), 7.52 (1 H, dd, J=2.4, 8.7 Hz), 7.42-7.26 (9H, in), 7.07 (lH, d, J=2.4 Hz), 6.70 (1H, d, J=8.3 Hz), 5.35 (IH, d, J=8.4 Hz), 5.14 (2H, ABq, J=19.6 Hz), 3.47 (3H, s).
1 3 C NMR (75 MHz, CDCl 3 5 166.66, 165.65, 155.72, 140.52, 136.99, 136.0, 132.87, 131.99, 131.47, 131.40, 131.38, 131.16, 130.54, 130.06, 128.45, 128.08, 128.03, 127.72, 127.22, 123.28, 122.01, 68.95, 67.02, 35.32.
Step B Preparation of 3-Amino-7-chloro- 1 3-dihydro-l1-methyl-5-(2ch1nrnnh~nv1'~-2H-1 4-hen7ndiazenin-2-nne chloronhenvl)-2H-1 4-benzodiazenin-2-one WO 98/28268 PCT/US97/22986 340-- Following General Procedure 8-B3 using 3-(benzyloxycarbonyl)-amino-7chloro-2,3-dihydro- I-methyl-5-(2-chlorophenyl)-I1H-i ,4-benzodiazepin-2-one, the title intermediate was prepared as a white foam which was used immediately in Step C.
Step C Preparation of 3 N' -(tert-Butvlcarbamate)-L-alaniny 11-amino- 7-chioro- I .3-dihvdro- 1 -methyl-5-(2-chlorop~henyl)-2H- 1.4benzodiazepin-2-one Following General Procedure D using N-Boc-L-alanine and 3-amnino-7chloro-1I,3-dihydro-lI-methyl-5-(2-chlorophenyl)-2H-1I,4-benzodiazepin-2-one, the title intermediate was prepared as a white foam.
C
24
H
26 Cl2N 4 0 4 (MW 505.44); mass spectroscopy 505.2.
Step D Preparation of 3-(L-Alaninvl)-amino-7-chloro- 1 3-dihydro- 1methyl-5-(2-chlorophenvl)-2H- 1 .4-benzodiazetpin-2-one Following General Procedure 8-C using 3- -Qert-butylcarbamate)-Lalaninyl]-amino-7-chloro- 1,3-dihydro-lI-methyl-5-(2-chlorophenyl)-2H- 1,4benzodiazepin-2-one, the title intermediate was prepared as a white foam. The crude material was used immuediately.
Example 8-G Synthesis of 3-(L-Alaninyl)amino-5-cyclohexyl-2,3-dihydro- 1-rn thyl-1H-1 ,4-Benzodiazepin-2-one Step A Prep~aration of 2.3-dihydro- 1-methyl-I H-I .4-benzodiazepin-2-one Following General Procedure 8-A using cyclohexyl-2,3-dihydro- 1H-I ,4-benzodiazepin-2-one (Neosystem), the title intermediate was prepared as a white solid having a melting point of 205-206'C.
C 4
H,
7
N
3 0 3 (MW =405.54); mass spectroscopy 405.
'H NMR (300 MHz, CDCl 3 8 7.54 (IR, d, J=7.9 Hz), 7.48 (1H, d, J=7.7 Hz), 7.36-7.26 (7H, in), 6.54 (IH, d, J= 8.3 Hz), 5.15 (lH, d, J=8.0 Hz), 5.09 WO 98/28268 PCTIUS97/22986 341 (2H, ABq, J=17.1 Hz), 3.39 (3H, 2.77 (lH, in), 2.01 (lH, bd, J=13.6 Hz), 1.85 (iN, bd, J=12.4 Hz), 1.68-1.49 (4H, in), 1.34-1.02 (4H, in).
Step B Preparation of 3 -Amino-5-cvclohexyl- 1 3-dihydro-l1-methyl- 2H- 1 .4-benzodiazepin-2-one Following General Procedure 8-B using cyclohexyl-2,3-dihydro- 1-methyl-i H-I ,4-benzodiazepin-2-one, the title intermediate was prepared as a white foam which was used immediately in Step
C.
C
16
H,,N
3 0 (MW+H 272.1763); mass spectroscopy 272.1766 Step C Preparation of 3 [N'-(er-Butlcarbaiate)-L-alaninylI -amino- 5-cyclohexyl-1I 3-dihvdro-lI-methyl-2H-1I 4-benzodiazepin-2one Following General Procedure D using N-Boc-L-alanine and cyclohexyl-1I,3-dihydro- 1-methyl-2H-1I,4-benzodiazepin-2-one, the title intermediate was prepared as a white foam.
C
24
H
3 4
N
4 0 4 (MW 442.62); mass spectroscopy 443.2.
Step D Preparation of 3-(L-Alaninyl)amino-5-cvclohexvl-1I.3-dihydro- I -methyl-2H- I A-benzodiaze]pin-2-one Following General Procedure 8-C using 3- -(tert-butylcarbamate)-L- 1 ,3-dihydro- 1 -methyl-2H- 1 ,4-benzodiazepin-2-one, the title intermediate was prepared as a white foam. The crude material was used immediately.
C
19
H,
6
N
4 0,1 (M+H 343.2136); mass spectroscopy found 343.2139.
Example 8-H Synthesis of 3-(L-Alaninyl)amino-2,3-dihydro-l-methyl- 7-nitro-5-phenyl-1 H-1,4-benzodiazepin-2-one Step A Preparation of 2-[N-(a-Isopronylthio)-N'- WO 98/28268 PCTUS97/22986 342 A solution of a-(isopropylthio)-N-(benzyloxycarbonyl)glycine (1 eq; prepared according to Zoller, Ben-Ishai, D. Tetrahedron 1975, 31, 863.) in dry THF was cooled to 0 *C and treated with oxalyl chloride (1 eq.) and 3 drops of DMF. After stirring for 15 minutes at 0°C, the cooling bath was removed and stirring continued at ambient temperature for 40 minutes. The solution was recooled to 0°C. A solution of 2-amino-5-nitrobenzophenone (0.9 eq.; Acros) and 4-methylmorpholine (2.0 eq.) in dry THF was added via cannulation to the acid chloride. The cooling bath was removed and the reaction stirred at ambient for 5 hours. The reaction was diluted with methylene chloride and washed with 0.5 M citric acid, saturated aqueous NaHCO 3 and brine. The organic phase was dried over Na 2
SO
4 filtered, and concentrated. The residue was purified via preparative LC2000 eluting with a gradient of 15-,20% ethyl acetate/hexanes giving an off-white foam.
C
26
H
5
N
3 0 6 OS (MW 507.61); mass spectroscopy found 507.9.
Anal. calcd for C 2 6
H
5
N
3 0 6 OS: C, 61.53; H, 4.96; N, 8.28. Found: C, 61.70; H, 4.99; N, 8.22.
Step B Preparation of 2-[N-(a-Amino)-N'-(benzvloxvcarbonvl)- Ammonia gas was bubbled into a solution 2-[N-(a-isopropylthio)-N'- (1 eq) in THF at 0°C.
After 35 minutes mercury(II) chloride (1.1 eq) was added. The ice bath was removed and ammonia gas was continued to bubble through the suspension for 4 hours. The bubbler was removed and the reaction continued to stir for 16 hours.
The mixture was filtered through celite washing with THF. The filtrate was concentrated in vacuo. The crude solid was used in step C without further purification.
Step C Preparation of 3-(Benzvloxvcarbonvl)-amino-2.3-dihvdro-7nitro-5-phenvl-1 H- 1,4-benzodiazepin-2-one nitrobenzophenone (1 eq) was treated with glacial acetic acid and ammonium WO 98/28268 PCTIUS97/22986 acetate (4.7 eq). The suspension was stirred at ambient temperature for 21 hours. After concentrating the reaction in vacuo, the residue was partitioned between ethyl acetate and 1 N NaOH. The aqueous layer was back-extracted with ethyl acetate. The combined organics were washed with brine, dried over Na 2
SO
4 filtered, and concentrated. The residue was purified via flash chromatography eluting with a gradient of isopropyl alcohol/methylene chloride.
C,
3
H,
8
N
4 0 5 (MW 430.45); mass spectroscopy found 431.2.
Anal. calcd for C 23
H,
8
N
4 0 5 C, 64.18; H, 4.22; N, 13.02. Found: C, 64.39; H, 4.30; N, 13.07.
Step D Preparation of 3-(Benzvloxvcarbonvl)-amino-2,3-dihvdro-l- I H- 1,4-benzodiazepin-2-one Following General Procedure 8-A and using 3-(benzyloxycarbonyl)-amino- 2,3-dihydro-7-nitro-5-phenyl- IH-I ,4-benzodiazepin-2-one, the title intermediate was prepared as a yellow foam.
C
2 4
H
20
N
4 0 5 (MW 444.48); mass spectroscopy found 445.2.
Anal. calcd for C, 4
H
20
N
4 0 5 C, 64.86; H, 4.54; N, 12.60. Found: C, 65.07; H, 4.55; N, 12.46.
Step E Preparation of 3 -Amino- 13 -dihydro- I-methvl-7-nitro-5 12henyl-2H- I .4-benzodiazep~in-2-one Following General Procedure 8-B and using 3-(benzyloxycarbonyl)-amino- 2,3-dihydro-l1-methyl-7-nitro-5-phenyl- IH-i ,4-benzodiazepin-2-one, the title intermediate was prepared as a yellow foam which was used immediately in Step F.
Step F Preparation of 3-rN'-(tert-Butvlcarbamate) -L-alaninyl l-amino- 2,3-dihydro-l1-methyl-7-nitro-5-phenvl- IH-I .4-benzodiazepin- 2-one Following General Procedure D using N-Boc-L-alanine and 3-amino-1,3dihydro-lI-methyl-7-nitro-5-phenyl-2H- 1,4-benzodiazepin-2-one, the title intermediate was prepared as a yellow solid.
WO 98/28268 PCT~IUS97/22986 3"4--
C,-
4
H-
7
N
5 0 6 (MW 481.56); mass spectroscopy found 482.3.
Anal. calcd for C2 4
H
2 7
N
5 0 6 C, 59.88; H, 5.61; N, 14.55. Found: C, 60.22; H, 5.75; N, 13.91.
Step G Preparation of 3-(L-Alaninvl)-amino-2.3-dihydro-lI-methyl-7- -phenyl- 1H-I A-benzodiazepin-2-one Following Gen eral Procedure 8-C using 3- -(ter-butylcarbamate)-Lalaninyl]-amino-2,3-dihydro- 1 -methyl-7-nitro-5-phenyl- 1 H-I ,4-benzodiazepin-2one, the title intermediate was prepared as a yellow foam. The crude material was used immediately.
Example 8-1 Synthesis of 3-(L-Alaninyl)amino-2,3-dihydro- I1-m ethyl- 5-(2-fluorophenyl)-lH-1,4-benzodiazepin-2-one Step A Preparation of 3 -Amino- 13 -dihydro-1I-methyl-5(2 fluorophenyl)-2H- 1.4-benzodiazepin-2-one A flask was charged with 3-(benzyloxycarbonyl)-amino-7-bromo-2,3dihydro-l1-methyl-5-(2-fluorophenyl)- 1H-I ,4-benzodiazepin-2-one (I eq.; Example Step A) and 10% palladium on carbon. Methanol was added, and the flask was placed under a balloon of H 2 The reaction was stirred for 21 hours. The mixture was filtered through celite washing with methanol. The filtrate was concentrated to a white solid.
C
16
H
14
FN
3 0 (MW =283.33); mass spectroscopy found 284.1.
Step B Preparation of 3 -[N'-(ter-Butvlcarbamate)-L-alaninlI -amino- I .3-dihydro- I -methyl-5-(2-fluorophenvl)-2H- I Abenzodiazepin-2-one Following General Procedure D using N-Boc-L-alanine and 3-amino- 1,3dihydro-l1-methyl-5-(2-fluorophenyl)-2H-1I,4-benzodiazepin-2-one, the title intermediate was prepared as a white solid.
C.,
4
H'
7
FN
4 ,0 4 (MW 454.50); mass spectroscopy found 455.4.
Anal. calcd for C, 4
H
27
FN
4 0 4 C, 63.44; H, 5.95; N, 12.33. Found: C, 63.64; H, 6.08; N, 12.16.
WO 98/8268 PCTIUS97/22986 345 Step C Preparation of 3-(L-Alaninvl)-amino-7-bromo-1I 3-dihydro- Imethvl-5-(2-fluorophenvl)-2H-1I 4-benzodiazepin-2-one Following General Procedure 8-C using 3-[N'-(tert-butylcarbamate)-Lalaninyl] -amino- 1, ,3-dihydro- 1 -methyl-5-(2-fluorophenyl)-2H- 1 ,4-benzodiazepin- 2-one, the title intermediate was prepared as a white foam. The crude material was used immediately.
Example 8-J Synthesis of 3-(L-Alaninyl)-amino-2,3-dihydro- 1-methyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepin-2-one Step A Preparation of 2-Amino-3'-fluorobenzop~henone A solution of 3-bromofluorobenzene (I eq.) in THF was cooled to -78*C under nitrogen and treated with tert-butyllithiumn (2.05 eq., 1.6 M solution in pentane) at a rate of 40 mI/h. The internal temperature did not rise above 74'C. The orange solution was stirred at -78*C for 30 minutes prior to the addition of anthranilonitrile (0.6 eq.) as a solution in THF. The reaction was warmed to 0 0 C and stirred for 2 hours. 3N HCl was added to the mixture and stirring continued for 30 minutes. The reaction was diluted with ethyl acetate and the layers were separated. The aqueous layer was back-extracted thrice with ethyl acetate. The combined extracts were washed with brine, dried over Na 2
SO
4 filtered, and concentrated. The residue was purified via HPLC eluting with 93:7 hexanes/ethyl acetate.
C1 3 Hj 0 FNO (MW 215.24); mass spectroscopy found 216.3.
'H NMR (300 MHz, CDCl 3 d 7.44-7.19 (6H, in), 6.74 (lH, d, J=8.0 Hz), 6.61 (lH, dd, J=0.94, 7.9 Hz), 6.10 (2H, bs).
Step B Preparation of 2-rN-(cc-Isopropvlthio)-N'- (benzvloxvcarbogyl)-Plvcinll-amino-3 '-fluorobenzop2henone A solution of a-(isopropylthio)-N-(benzyloxycarbonyl)glycine (1 eq; prepared according to Zoller, Ben-Ishai, D. Tetrahedron 1975, 31, 863.) in dry THF was cooled to 0 0 C and treated with oxalyl chloride (I eq.) and 3 drops of DMF. After stirring for 15 minutes at 0 0 C, the cooling bath was removed WO 98/28268 PCT/US97/22986 346 and stirring continued at ambient temperature for 40 minutes. The solution was recooled to 0 C. A solution of 2 -amino-3'-fluorobenzophenone (0.9 eq.) and 4methylmorpholine (2.0 eq.) in dry THF was added via cannulation to the acid chloride. The cooling bath was removed and the reaction stirred at ambient for 5 hours. The reaction was diluted with methylene chloride and washed with M citric acid, saturated aqueous NaHCO 3 and brine. The organic phase was dried over Na,SO,, filtered, and concentrated. The residue was purified via preparative LC2000 eluting with a gradient of 15-+20% ethyl acetate/hexanes giving an off-white foam.
C,
6
H,
5
N
2 0 4 S (MW 480.60); mass spectroscopy found (M+NH 4 498.3.
'H NMR (300 MHz, CDCl 3 d 11.39 (1H, 8.59 (1H, d, J=6.0 Hz), 7.63- 7.55 (2H, 7.48-7.27 (9H, 7.14 (1H, dt, J=1.2, 8.4 Hz), 5.94 (1H, d, J=7.2 Hz), 5.58 (1H, d, J=8.7 Hz), 5.17 (2H, ABq, J=14.7 Hz), 3.25 (1H, sep, J=6.6 Hz), 1.44 (3H, d, J=6.0 Hz), 1.28 (3H, d, J=6.6 Hz).
Step C Preparation of 2-[N-(a-Amino)-N'-(benzvloxvcarbonyl)glvcinvll-amino-3'-fluorobenzophenone Ammonia gas was bubbled into a solution 2-[N-(a-isopropylthio)-N'- (benzyloxycarbonyl)-glycinyl]-amino-3'-fluorobenzophenone (1 eq) in THF at 0°C. After 35 minutes mercury(II) chloride (1.1 eq) was added. The ice bath was removed and ammonia gas was continued to bubble through the suspension for 4 hours. The bubbler was removed and the reaction continued to stir for 16 hours. The mixture was filtered through celite washing with THF. The filtrate was concentrated in vacuo. The crude solid was used in step D without further purification.
Step D Preparation of 3-(Benzvloxycarbonvl)-amino-2.3-dihvdro-5- (3-fluorophenyl)-1 H-1,4-benzodiazepin-2-one 2-[N-(a-Amino)-N'-(benzyloxycarbonyl)-glycinyl]-amino-3'fluorobenzophenone (1 eq) was treated with glacial acetic acid and ammonium acetate (4.7 eq). The suspension was stirred at ambient temperature for 21 hours. After concentrating the reaction in vacuo, the residue was partitioned WO 98/28268 PCTIUS97/22986 347 between ethyl acetate and I N NaGH. The aqueous layer was back-extracted with ethyl acetate. The combined organics were washed with brine, dried over Na,S0 4 filtered, and concentrated. The residue was purified via flash chromatography eluting with a gradient of isopropyl alcohol/methylene chloride.
C
23
H
18
FN
3 0 3 (MW 403.44); mass spectroscopy found 404.4.
Anal. calcd for C, 3
H
18
FN
3 0 3 *0.5H,O: C, 66.98; H, 4.64; N, 10.18. Found: C, 67.20; H, 4.64; N, 9.77.
Step E Preparation of 3-(Benzvloxycarbonyl)-amino-2,3-dihydro-lmethvl-5-(3-fluorophenvl)- IH-I .4-benzodiazepin-2-one Following General Procedure 8-A and using 3-(benzyloxycarbonyl)-anuno- 2,3-dihydro-5-(3-fluorophenyl)- 1H-I ,4-benzodiazepin-2-one, the title intermediate was prepared as a yellow foam.
C 4
H-,
0
FN
3 0 3 (MW 417.47); mass spectroscopy found 418.3.
Anal. calcd for C 24
H
20
FN
3 0 3 C, 69.06; H, 4.83; N, 10.07. Found: C, 69.33; H, 4.95; N, 9.82.
Step F Preparation of 3-Amino-l,3-dihydro-l-methvl-5-(3fluorop~henvl)-2H- I ,4-benzodiazepin-2-one Following General Procedure 8-B and using 3-(benzyloxycarbonyl)-amino- 2,3-dihydro-l1-methyl-5-(3-fluorophenyl)- 1H-I ,4-benzodiazepin-2-one, the title intermediate was prepared as a yellow foam which was used immediately in Step G.
Step G Preparation of 3-IN' -(er-Butlcarbamate)-L-alaninylI -amino- 2,3-dihydro- 1 -methvl-5-(3-fluorophenvl)- I H- 1.4benzodiazeyin-2-one Following General Procedure D using N-Boc-L-alanine and 3-arnino-1,3dihydro-lI-methyl-5-(3-fluorophenyl)-2H- 1,4-benzodiazepin-2-one, the title intermediate was prepared as a yellow solid.
C,,H,,FN
4 0 4 (MW =454.50); mass spectroscopy found 455.3.
WO 98/8268 PCT/US97/22986 348 Anal. calcd for C, 4
H,
7
FN
4 0 4 C, 63.42; H, 5.99; N, 12.33. Found: C, 63.34; H, 6.01; N, 12.08.
Step H Preparation of 3-(L-Alaninvl)-amino-2,3-dihydro-l1-methyl-5- (3-fluorophenyl)- 1 H-I 1.-benzodiazepin-2-one Following General Procedure 8-C using 3-[N'-(tert-butylcarbaniate)-Lalaninyl]-amino-2,3-dihydro- 1 -methyl-5-(3-fluorophenyl)- 1 H-I ,4-benzodiazepin- 2-one, the title intermediate was prepared as a yellow foam. The crude material was used immediately.
Example 8-K Synthesis of 3-(L-Alaninyl)amino-2,3-dihydro-1-methyl- 5-(4-fluorophenyl)-1H-1 ,4-benzodiazepin-2-one Step A Preparation of 2 -Amino-4'-fluorobenzophenone A solution of 4-bromofluorobenzene (I eq.) in THF was cooled to -78*C under nitrogen and treated with tert-butyllithium (2.05 eq., 1.6 M solution in pentane) at a rate of 40 ml/h. The internal temperature did not rise above 74"C. The orange solution was stirred at -78*C for 30 minutes prior to the addition of anthranilonitrile (0.6 eq.) as a solution in THF. The reaction was warmed to 0 0 C and stirred for 2 hours. 3N HCl was added to the mixture and stirring continued for 30 minutes. The reaction was diluted with ethyl acetate and the layers were separated. The aqueous layer was back-extracted thrice with ethyl acetate. The combined extracts were washed with brine, dried over Na,S0 4 filtered, and concentrated. The residue was purified via HPLC eluting with 93:7 hexanes/ethyl acetate.
C
13 Hj 0 FN0 (MW =215.24); mass spectroscopy found 216.3.
Anal. calcd for C 13 HjOFNO: C, 72.55; H, 4.68; N, 6.51. Found: C, 72.80; H, 4.5 1; N, 6.74.
Step B Preparation of 2-[N-(ct-Isopropylthio)-N'- (benzvloxvcarbonvl)-2lycinyll-amino-4' -fluorobenzophenone WO 98/28268 PCT/US97/22986 349 A solution of a-(isopropylthio)-N-(benzyloxycarbonyl)glycine (1 eq; prepared according to Zoller, Ben-Ishai, D. Tetrahedron 1975, 31, 863.) in dry THF was cooled to 0 C and treated with oxalyl chloride (1 eq.) and 3 drops of DMF. After stirring for 15 minutes at 0 C, the cooling bath was removed and stirring continued at ambient temperature for 40 minutes. The solution was recooled to 0°C. A solution of 2-amino-4'-fluorobenzophenone (0.9 eq.) and 4methylmorpholine (2.0 eq.) in dry THF was added via cannulation to the acid chloride. The cooling .bath was removed and the reaction stirred at ambient for hours. The reaction was diluted with methylene chloride and washed with M citric acid, saturated aqueous NaHCO 3 and brine. The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified via preparative LC2000 eluting with a gradient of 15-+20% ethyl acetate/hexanes giving an off-white foam.
C
26
H-,
5 N0 4 S (MW 480.60); mass spectroscopy found (M+NH 4 498.2.
'H NMR (300 MHz, CDCI 3 d 11.28 (1H, 8.56 (1H, d, J=8.4 Hz), 7.78- 7.73 (2H, 7.61-7.53 (2H, 7.36-7.32 (5H, 7.20-7.14 (3H, 5.98 (1H, d, J=7.5 Hz), 5.57 (1H, d, J=7.8 Hz), 5.16 (2H, ABq, J=14.7 Hz), 3.25 (1H, sep, J=6.0 Hz), 1.43 (3H, d, J=6.3 Hz), 1.27 (3H, d, J=6.6 Hz).
Step C Preparation of 2-rN-(-Amino)-N'-(benzvloxvcarbonvl)glvcinvll-amino-4'-fluorobenzophenone Ammonia gas was bubbled into a solution 2-[N-(a-isopropylthio)-N'- (benzyloxycarbonyl)-glycinyl]-amino-3'-fluorobenzophenone (1 eq) in THF at 0°C. After 35 minutes mercury(II) chloride (1.1 eq) was added. The ice bath was removed and ammonia gas was continued to bubble through the suspension for 4 hours. The bubbler was removed and the reaction continued to stir for 16 hours. The mixture was filtered through celite washing with THF. The filtrate was concentrated in vacuo. The crude solid was used in step D without further purification.
Step D Preparation of 3 -(Benzvloxvcarbonvl)amino-2.3-dihvdro-5-(4fluorophenyl)-1 H- 1,4-benzodiazepin-2-one WO 98/28268 PTU9128 PCTIUS97/22986 350 2-[N-(cc-Amino)-N' -(benzyloxycarbonyl)-glyciny1]-amino-4' fluorobenzophenone (1 eq) was treated with glacial acetic acid and ammonium acetate (4.7 eq). The suspension was stirred at ambient temperature for 21 hours. After concentrating the reaction in vacuo, the residue was partitioned between ethyl acetate and I N NaOH. The aqueous layer was back-extracted with ethyl acetate. The combined organics were washed with brine, dried over Na,S0 4 filtered, and concentrated. The residue was purified via flash chromatography eluting with a gradient of isopropyl alcohol/methylene chloride.
C
23
H
18
FN
3 0 3 (MW 403.44); mass spectroscopy found 404.4.
Anal. calcd for C, 3
H,
8
FN
3 0 3 *l.25H,O: C, 64.85; H, 4.85. Found: C, 64.80; H, 4.55.
Step E Preparation of 3 -(Benzloxvcarbonvl)-amino-2,3-dihydro-1 methvl-5-(4-fluorophenyl)- I H-i 1,4-benzodiazepin-2-one Following General Procedure 8-A and using 3-(benzyloxycarbonyl)-amino- 2,3 -dihydro-5-(4-fluorophenyl)- 1H-i ,4-benzodiazepin-2-one, the title intermediate was prepared as a yellow foam.
C,1 4
H,
0
FN
3 0 3 (MW 417.47); mass spectroscopy found 418.2.
Anal. calcd for C, 4
H,
0
FN
3 0 3 C, 69.06; H, 4.83; N, 10.07. Found: C, 69.35; H, 4.93; N, 9.97.
Step F Preparation of 3 -Amino- 1,3-dihydro- I methyl-5-(4fluorophenyl)-2H- 1 .4-benzodiazepin-2-one Following General Procedure 8-B and using 3-(benzyloxycarbonyl)-amino- 2,3 -dihydro- 1-methyl-5-(4-fluorophenyl)- 1H-i ,4-benzodiazepin-2-one, the title intermediate was prepared as a yellow foam which was used immediately in Step G.
Step G Preparation of 3 -N'-(ert-Butlcarbamate)-L-alaninyI I-amino- 2,3-dihydro- I -methvl-5-(3-fluorophenyl)- I H- 1,4benzodiazepin-2-one WO 98/28268 PTU9/28 PCTIUS97t22986 351 Following General Procedure D using N-Boc-L-alanine and 3-amino- 1,3dihydro-l1-methyl-5-(3-fluorophenyl)-2H-1I,4-benzodiazepin-2-one, the title intermediate was prepared as a yellow solid.
C,
4 H VFN 4 0 4 (MW 454.50); mass spectroscopy found 455.4.
Anal. calcd for C, 24
H
27
FN
4 0 4 1 .511,O: C, 59.86; H, 6.28; N, 11.64. Found: C, 60.04; H, 5.62; N, 11.27.
Step H Preparation of 3-(L-Alaninvl)-amino-2,3 -dihydro- (4-fluorophenyl)- 1 H- 1,4-benzodiazeipin-2-one Following General Procedure 8-C using 3-[N'-(tert-butylcarbamat6)-Lalaninyl]-amino-2,3-dihydro-lI-methyl-5-(4-fluorophenyl)- 1H-i ,4-benzodiazepin- 2-one, the title intermediate was prepared as a yellow foam. The crude material was used immediately.
Example 8-L Synthesis of 3-(N '-L-Alaninyl)amino-2,3-dihydro-1-isobutyl- 5-phenyl-1 H-1,4-benzodiazepin-2-one Step A: 1 ,3-Dihydro-5-phenyl-2H- 1,4-benzodiazepin-2-one (prepared according to the procedure of M. G. Bock et al., J1 Org. Chem. 1987, 52, 3232- 3239) was alkylated with isobutyl iodide using General Procedure 8-G to afford 1 ,3-dihydro-lI-isobutyl-5-phenyl-2H- 1,4-benzodiazepin-2-one.
Step B: Following General Procedures 8-D and 8-F and using the product from Step A, 3 -amino- 1,3 -dihydro- 1 -isobutyl-5 -phenyl-2H- I ,4-benzodiazepin-2one was prepared.
Step2 C: The product from Step B and N-Boc-L-alanine (Sigma) were coupled using General Procedure D, followed by removal of the Boc group using General Procedure 8-J, to afford 3-(N'-L-alaninyl)amino-1,3-dihydro-lisobutyl-5-phenyl-2H-1I,4-benzodiazepin-2-one.
WO 98/28268 PCTIUS97t22986 352 By substituting isopropyl iodide, n-propyl iodide, cyclopropylmethyl iodide and ethyl iodide for isobutyl iodide in Step A above, the following additional intermediates were prepared: 3-(N'-L-alaninyl)amino-1I,3-dihydro-l1-isopropyl-5-phenyl-2H- 1,4benzodiazepin-2-one 3-(N'-L-alaninyl)aniino-1I,3-dihydro-lI-propyl-5-phenyl-2H- 1,4benzodiazepin-2-one 3 -(N'-L-alaninyl)amino- 1,3-dihydro- I-cyclopropylmethyl-5-phenyl-2H- 1,4benzodiazepin-2-one 3-(N'-L-alaninyl)amnino- 1 ,3-dihydro- I -ethyl- 5-phenyl-2H- 1 ,4-benzodiazepin- 2-one.
Example 8-M Synthesis of 3-(N'-L-Alaninyl)amino-1-methyl-5-phenyl- 1 ,3,4,5-tetrahydro-2H-1 ,5-benzodiazepin-2-one Step2 A: 1 ,3,4,5-Tetrahydro-5-phenyl-2H- 1,5-benzodiazepin-2-one (CAS No.
32900-17-7) was methylated using General Procedure 8-1 to afford 1 phenyl- 1,3 ,4,5-tetrahydro-2H- 1 ,5-benzodiazepin-2-one.
Step B: Following General Procedures 8-B and 8-F and using the product from Step A, 3 -amino- 1 -methyl-5-phenyl- 1, 3,4,5-tetrahydro-2H- 1,5 benzodiazepin-2-one was prepared.
Step C: The product from Step B and N-Boc-L-alanine (Sigma) were coupled using General Procedure D, followed by removal of the Boc group using General Procedure 8-N, to afford 3-(N'-L-alaninyl)amino-1-methyl-5phenyl- 1,3 ,4,5-tetrahydro-2H- 1 ,5-benzodiazepin-2-one.
Example 8-N Synthesis of 3-(N'-L-Alaninyl)amino-2,4.dioxo- 2,3,4,5-tetrahydro-1 H-i WO 98/28268 PCTIUS97/22986 -353 3-Amino-2,4-dioxo- I -methyl-5-phenyl-2.3 ,4,5-tetrahydro- 1 H- benzodiazepine (CAS No. 131604-75-6) was coupled with N-Boc-L-alanine (Sigma) using General Procedure D, followed by removal of the Boc group using General Procedure 8-N, to afford the title compound.
Example Synthesis of 3-((R)-Hydrazinopropionyl)amino-2,3-dihydro- 1 -methyl-5-phenyl)- 1H-i ,4-benzodiazepin-2-one 3-Amino-2,3-dihydro-lI-methyl-5-phenyl- 1H-i ,4-benzodiazepin-2-one was coupled to (R)-N,N'-di-BOC-2-hydrazinopropionic acid (Example N) using General Procedure D. Removal of the Boc group using General Procedure afforded the title compound.
Example 8-P Synthesis of 3-Amino-2,4-dioxo-1 ,5-bis-(l1-methylethyl)- 2,3,4,5-tetrahydro-1 H-i Step A: Synthesis of 2,4-Dioxo-2,3,4,5-tetrahydro-lH-1,5benzodiazepine 2,4-Dioxo-2,3 ,4,5-tetrahydro- 1H-i ,5-benzodiazepine (CAS No. 49799-48-6) was prepared from 1 ,2-phenylenediamine (Aldrich) and malonic acid (Aldrich) using the procedure of Claremon, D. et al, PCT Application: WO 96- US8400 960603.
Step B: Synthesis of 2,4-Dioxo-1,5-bis-(1-methylethyl)-2,3,4,5tetrahydro-1 H-i 2,4-Dioxo- 1,5-bis-( I-methylethyl)-2,3 ,4,5 -tetrahydro- IH- (CAS No. 113021-84-4) was prepared following General Procedure 8-M using the product from Step A and 2-iodopropane (Aldrich). Purification was by flash chromatography eluting with EtOAc/hexanes gradient to then recrystalization from EtOAc/hexanes.
WO 98/28268 PCT/US97/22986 354 Step C: Synthesis of 3-Azido-2,4-dioxo-1,5-bis-(1-methylethyl)- 2,3,4,5-tetrahydro-1 H-i Following General Procedure 8-K using the product from Step B, 3-azido- 2,4-dioxo- 1,5-bis-( 1-methylethyl)-2,3 ,4,5-tetrahydro- 1H-I, (CAS No. 186490-50-6) was prepared as a white solid. The product was purified by flash chromatography eluting with hexanes/EtOAc to provide a separable 23:1 mixture of pseudo-axial/pseudo-equatorial azides. The pure pseudo-axial azide was used in the next step.
Step, D: Synthesis of 3 -Amino-2,4-dioxo-1,5-bis-(1-methylethy)- 2,3,4,5-tetrahydro-1 H-i Following General Procedure 8-L using the product from Step C, 3-amino- 2,4-dioxo- 1,5-bis-( 1-methylethyl)-2,3,4,5-tetrahydro- 1H-i (CAS No. 186490-51-7) was prepared as a white solid. Purification was by flash chromatography eluting with CH,C1 2 /MeOH (98:2 gradient to 95:5). The isolated pseudo-axial amine atropisomer was completely converted to the pseudo-equatorial amine atropisomer by heating in toluene to 100-105 0 C for minutes, and the pseudo-equatorial amnine atropisomer was used in the next step.
The isomers were distinguished by 'H-NMR in CDC 3 Selected 'H-NMR (CDCl 3 Pseudo-axial amine 4.40 IH); Pseudo-equatorial amine 3.96 (s, I1H).
Example 8-Q Synthesis of 3-(R-2-Thienylglycinyl)amino-2,4-dioxo- 1 ,5-bis-( 1-methylethyl)-2,3,4,5-tetrahydro- 1H-1,5-benzodiazepine Hydrochloride Step1 A: Synthesis of N-(t-Butoxycarbonyl)-R-2-thienylglycine N-(t-Butoxycarbonyl)-R-2-thienylglycine (GAS No. 74462-03-1) was prepared from L-ac-(2-thienyl)glycine (Sigma) by the procedure described in Bodansky, MA et al; The Practice of Peptide Synthesis; Springer Verlag; 1994, p.
17.
WO 98/28268 PCTIUS97/22986 Step B: Synthesis of 3 -IN'-(t-Butoxycarbonyl)-R-2-thienylglycinyl]amino-2,4-dioxo-1 ,5-bis-( 1-methylethyl)-2,3,4,5-tetrahydro- 1 H-i Following General Procedure J above using the product from Example 8-P and the product from Step A above, 3-[N'-(t-butoxycarbonyl)-R-2thienylglycinyl]-amino-2,4-dioxo- 1 ,5-bis-( I -methylethyl)-2,3,4,5-tetrahydro- 1 H- I ,5-benzodiazepine was prepared as a white foam. Purification was by flash chromatography eluting with CH,CI,/EtOAc (9:1 gradient to 5:1).
Step C: Synthesis of 3-(R-2-Thienylglycinyl)amino-2,4-dioxo-1,5bis-(1-methylethyl)-2,3,4,5-tetrahydro-1 H-i beozodiazepine Hydrochloride Following General Procedure 8-N above using the product from Step B, the title compound was prepared as a white solid.
Example 8-R Synthesis of 3-(L-Alaninyl)-amino-2,4-dioxo-1,5-bis-methyl- 2,3,4,5-tetrahydro- 1H- 1,5-benzodiazepine Hydrochloride Step A: Synthesis of 2,4-Dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro- 1 H-i 2,4-Dioxo- 1,5-bis-methyl-2,3,4,5-tetrahydro- 1H-I ,5-benzodiazepine (CAS No. 23954-54-3) was prepared following General Procedure 8-M using the product from Example 8-P, Step A and iodomethane (Aldrich). The white solid product precipitated during partial concentration of the reaction after work-up, and was isolated by filtration.
Sterp B: Synthesis of 3-Azido-2,4-dioxo-i ,5-bis-methyl-2,3,4,5tetrahydro-1 For this substrate, General Procedure 8-K was modified in the following manner. Initially the product from Step A was suspended (not a solution) in THF at -78 0 C, and following addition of the KN(TMS), solution, this suspension was allowed to warm to -35 0 C over a period of 12 minutes, during which the suspension became a solution, and was re-cooled to -78 0 C; then WO 98/28268 PCTIUS97/22986 treated as described in the General Procedure. 3-Azido-2,4-dioxo-l,5-bismethyl-2,3,4,5-tetrahydro- 1H-I ,5-benzodiazepine was purified by flash chromatography eluting with CHCl 3 /EtOAc then trituration from hot
CHCI
3 with hexanes and cooled to -23*C. The product was isolated as a white solid.
Step C: Synthesis of 3-Amino-2,4-dioxo-l,5-bis-methyl-2,3,4,5tetrahydro-1 H-i Following General Procedure 8-L, using the product from Step B, 3-amino- 2,4-dioxo-1I,5-bis-methyl-2,3 ,4,5-tetrahydro- 1H-i ,5-benzodiazepine was prepared as a white solid. The crude product was used without further purification.
Step D: Synthesis of 3- IN'-(t-Butoxycarhonyl)-L-alaninylJ -amino- 2,4-dioxo-1 ,5-bis-methyl-2,3,4,5-tetrahydro- benzodiazepine Following General Procedure I above using N-Boc-L-alanine (Novabiochem) and the product from Step C, 3-[N'-(t-butoxycarbonyl)-Lalaninyl]-amino-2,4-dioxo- 1 ,5-bis-methyl-2,3 ,4,5-tetrahydro- I H- benzodiazepine, was prepared as a white foam. Purification was by flash chromatography eluting with CH,C1,/EtOAc (2:1 gradient to 1:1).
Step2 E: Synthesis of 3-(L-alaninyl)-amino-2,4-dioxo- 1,5-bis-m ethyl- 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine Hydrochloride Following General Procedure 8-N above using the product from Step D, the title compound was prepared as an off-white amorphous solid.
Example 8-S Synthesis of 3-(L-Alaninyl)amino-2,4-dioxo- 1,5-bis-(2-methylpropyl)- 2,3,4,5-tetrahydro-1 H-i ,5-henzodiazepine Hydrochloride Step A: Synthesis of 2,4-Dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5tetrahydro-1 2,4-Dioxo- 1,5-bis-(2-methylpropyl)-2,3 ,4,5-tetrahydro- 1H- benzodiazepine was prepared following General Procedure 8-M using the WO 98/28268 PCTIUS97/22986 357 product from Example 8-P, Step A and 1 -iodo-2-methylpropane (Aldrich).
Purification was by flash chromatography eluting with EtOAc/hexanes (3:7 gradient to then recrystalization from EtOAc/hexanes.
Step B: Synthesis of 3-Azido-2,4-dioxo-1,5-bis-(2-methylpropyl)- 2,3,4,5-tetrahydro-lH-1 Following General Procedure 8-K (a precipitate formed during the addition of the KN(TMS) 2 but dissolved upon addition of the trisyl azide) using the product from Step A, 3-azido-2,4-dioxo- 1,5-bis-(2-methylpropyl)-2,3 tetrahydro-1H-1 ,5-benzodiazepine was prepared as a white solid. The product was purified by flash chromatography eluting with hexanes/EtOAc and a second flash chromatography eluting with CH,Cl 2 lhexanes/EtOAc (10: 10: 1 gradient to 8:6: 1) Step C: Synthesis of 3-Amino-2,4-dioxo-1,5-bis-(2-methylpropyl)- 2,3,4,5-tetrahydro-1 H- Following General Procedure 8-L using the product from Step B, 3-amino- 2,4-dioxo- 1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro- 1H- 1,5-benzodiazepine was prepared as a white solid. Purification was by flash chromatography eluting with CH 2 C-,/MeOH (98:2 gradient to 95:5, with 5% NH 3 in the MeOH).
Step D: Synthesis of 3-IN'-(t-Butoxycarbonyl)-L-alaninylj -amino- 2,4-dioxo-1,5-his-(2-methylpropyl)-2,3,4,5-tetrahydro-1 H- 1 Following General Procedure I above using N-Boc-L-alanine (Novabiochem) and the product from Step C, 3-[N'-Q-butoxycarbonyl)-Lalaninyl]-amino-2,4-dioxo- 1,5-bis-(2-methylpropyl)-2,3 ,4,5-tetrahydro- IH- benzodiazepine was prepared as a white foam. Purification was by flash chromatography eluting with CH 2 C,/EtOAc (3:1 gradient to 3:2).
Step E: Synthesis of 3-(L-Alaninyl)-amino-2,4-dioxo-1,5-bis-(2methylpropyl)-2,3,4,5-tetrahydro-1 H-i Hydrochloride WO 98/28268 PCTIUS97t22986 358 Following General Procedure 8-N above using the product from Step D, the title compound was prepared as an amorphous white solid.
Example 8-T Synthesis of 3-(S-Phenylglycinyl)amino-2,4-dioxo-1,5-bis- 2 -methylpropyl)-2,3,4,5-tetrahydro- 1H-1,5-benzodiazepine Hydrochloride Step A: Synthesis of 3 -fN'-(t-Butoxycarbony)-S-phenylglycinyJ..
amino-2,4-dioxo-1,5-bis-(2-methyipropyl)-2,3,4,5tetrahydro-l1H-i Following General Procedure J above using the product from Example 8-S, Step C and the Boc-L-phenylglycine (Novabiochem, CAS No. 2900-27-8), 3- -(t-butoxycarbony)-S-phenylglycinyl]-amino2,4-dioxo- 1 ,5-bis-(2methylpropyl)-2,3 ,4,5-tetrahydro- 1H-i ,5-benzodiazepine was prepared as a white foam. Purification was by flash chromatography eluting with CH 2 Cl,/EtOAc (9:1 gradient to*5:1).
Step B: Synthesis of 3-SPeygyiy)aio24doo15bs 2 -methylpropyl)-2,3,4,5tetrahydrolH1,-benzodiazepine Hydrochloride Following General Procedure 8-N above using the product from Step A, 3- (S-phenylglycinyl)-amnino-2,4-dioxo- 1 ,5-bis-(2-methylpropyl)-2,3 ,4,S-tetrahydro- 1 H- 1,5-benzodiazepine hydrochloride was prepared as an off-white solid.
Example 8-U Synthesis of 3-(L-Alaninyl)amino-2,4-dioxo-1 2 3 4 ,5-tetrahydro-1H-1,5-benzodiazepine Hydrochloride Step2 A: Synthesis of 2 4 -Dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5tetrahydro- 1H-i 2,4-Dioxo- I ,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro- 1 H- benzodiazepine was prepared following General Procedure 8-M using the product from Example 8-P, Step A, and (bromomethyl)cyclopropane (Lancaster).
WO 98/28268 PCT1US97/22986 359 Purification was by flash chromatography eluting with EtOAc/hexanes (3:7 gradient to straight EtOAc), then recrystalization from EtOAc/hexanes.
Step B: Synthesis of 3-Azido-2,4-dioxo-1,5-bis-(cyclopropylmethyl)- 2,3,4,5-tetrahydro-lH-1,5-benzodiazepine For this substrate General Procedure 8-K was modified in the following manner. Initially the product from Step A was suspended (not a solution) in THF at -78 0 C, and following addition of the KN(TMS), solution, this suspension was allowed to warm to -30 0 C, during which the suspension became a solution, and was re-cooled to -78 0 C. Upon re-cooling to -78 0 C a precipitate began to form, therefore the reaction flask containing the mixture was partially raised above the cooling bath until the internal temperature rose to -50 0 C; then the trisyl azide solution was added. The cooling bath was removed and the mixture allowed to warm to -20 0 C whereupon the mixture had become a nearly homogenous solution, and the AcOH was added. Then, treated as described in the general procedure. 3-Azido-2,4-dioxo-l,5-bis-(cyclopropylmethyl)-2,3,4,5tetrahydro-1H-1,5-benzodiazepine was purified by trituration with hot to room temperature EtOAc, followed by recrystalization from hot to -23°C CHC1 3 /EtOAc/EtOH and isolated as a white solid.
Step C: Synthesis of 3-Amino-2,4-dioxo-l,5-bis- (cyclopropylmethyl)-2,3,4,5-tetrahydro-lH-1,5benzodiazepine Following General Procedure 8-L using the product from Step B, 3-amino- 2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H- was prepared as a white solid. Purification was by flash chromatography eluting with CHCl,/MeOH (98:2 gradient to 95:5, with 5% NH 3 in the MeOH) followed by recrystalization from warm CH,C1,/hexanes to -23 C.
Step D: Synthesis of 3-[N'-(t-Butoxycarbonyl)-L-alaninyl]-amino- 2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro- 1H-1,5-benzodiazepine WO 98/U8268 PCTIUS97/22986 360 Following General Procedure I above using N-Boc-L-alanine (Novabiochem) and the product from Step C, 3-IIN'-(t-butoxycarbonyl)-Lalaninyl] -amino-2,4-dioxo-1I,5-bis-(cyclopropylmethyl)-2,3 ,4,5-tetrahydro-l1H- benzodiazepine was prepared as a white foam. Purification was by flash chromatography eluting with CH.,CI,/EtOAc (3:1 gradient to 2:1).
Step E: Synthesis of 3-(L-Alaninyl)-amino-2,4-dioxo-1,5-bis- (cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1 benzodiazepine Hydrochloride Following General Procedure 8-N above using the product from Step D, the title compound was prepared as an off-white solid.
Example 8-V Synthesis of 3-(L-Alaninyl)-amino-2,4-dioxo- 1,5-bis-(2,2-dimethylpropyl)- 2,3,4,5-tetrahydro-1 H-i ,5-benzodiazepine Hydrochloride Step A: Synthesis of 2,4-Dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5tetrahydro-1H-1,5-benzodiazepine To a stirred suspension of the product from Example 8-P, Step A (1.0 eq., 17.08 g) in DMSO (500 mL) at room temperature was added neopentyl iodide (43.01 g, 2.24 eq., Aldrich) and Cs 2
CO
3 (72.65 g, 2.3 eq., Aldrich). The resulting mixture was heated to 75'C for 30 minutes, then additional Cs2C0 3 (31.59 g, 1.0 eq.) was added and the mixture rapidly stirred at 75*C for 6 hours.
The mixture was allowed to cool and H,O (500 mL) and EtOAc (1000 mL) were added. The phases were partitioned and the organic phase washed with H,O (lx500 mL), I M aq. HCl (2x500 mL), and brine (1x500 mL). Then, the organic phase was dried over MgSO 4 1 filtered, concentrated, and purified by flash chromatography eluting with hexanes/EtOAc (3:2 gradient to 2:3) to ~provide 2,4-dioxo-1I,5-bis-(2,2-dimethylpropyl)-2,3 ,4,5-tetrahydro- IH- 1,5 benzodiazepine as a white solid.
Step B: Synthesis of 3-Azido-2,4-dioxo-1,5-bis-(2,2dimethylpropyl)-2,3,4,5-tetrahydro-1 H-i ,S-benzodiazepine WO 98t28268 PTU9128 PCTfUS97/22986 Following General Procedure 8-K using the product from Step A, 3-azido- 2,4-dioxo- 1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro- 1H-i was prepared as a white solid. The product was purified by flash chromatography eluting with hexanes/CH 2 CI,/EtOAc (10:5:1 gradient to 5:5:1) to provide a separable 13:1 mixture of pseudo-axial/pseudo-equatorial azides. The pure pseudo-axial azide was used in the next step. Selected 'H-NMR (CDCl 3 Pseudo-axial azide 5.12 1H); Pseudo-equatorial azide 4.03 1H).
Step C: Synthesis of 3-Amino-2,4-dioxo-1,5-bis-(2,2dinhethylpropyl)-2,3,4,5-tetrahydro-lH-1,5-benzodiazepine Following General Procedure 8-L using the product from Step B, 3-amino- 2,4-dioxo- 1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro- 1H-i was prepared as a white solid. Purification was by flash chromatography eluting with CH,Cl,IMeOH (98:2 gradient to 95:5, with 5% NH 3 in the MeOH). The isolated white solid product was identified as a -4:1 mixture of pseudo-axial and pseudo-equatorial amines atropisomers by 'H-NMR. The mixture was heated in toluene to 100 'C for 20 minutes, then re-concentrated to provide the pure pseudo-equatorial amine atropisomer, as a white solid, and this was for the next step. Selected 'H-NMR (CDCl 3 Pseudo-axial amnine 4.59 IH); Pseudoequatorial amine 4.03 1H).
Step D: Synthesis of 3- IN'-(t-Butoxycarbonyl)-L-alaninyll -amino- 2,4-dioxo-1 ,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro- 1 H-i Following General Procedure I above using N-Boc-L-alanine (Novabiochem) and the product from Step C, 3-[N'-(t-butoxycarbonyl)-Lalaninyl]-amino-2,4-dioxo- 1,5-bis-(2,2-dimethylpropyl)-2,3 ,4,5-tetrahydro- 1H- 1 ,5-benzodiazepine was prepared as a white foam. Purification was by flash chromatography eluting with CH-,C1 2 /EtOAc (4:1 gradient to 5:2).
Step E: Synthesis of 3-(L-Alaninyl)-amino-2,4-dioxo-1,5-bis-(2,2dimethylpropyl)-2,3,4,5-tetrahydro-1 Hydrochloride WO 98/28268 PCT/US97/22986 362 Following General Procedure 8-N above using the product from Step D, the title compound was prepared as an off-white solid.
Example 8-W Synthesis of 3-(L-Alaninyl)amino-2,4-dioxo-l,5-bis-phenyl- 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride Step A: Synthesis of 2 4 -Dioxo-l,5-bis-phenyl-2,3,4,5-tetrahydro- 1H-1,5-benzodiazepine This procedure is a modification of the procedure described in Chan, D. M.
T. Tetrahedron Lett. 1996, 37, 9013-9016. A mixture of the product from Example 8-P, Step A (1.0 eq., 7.50 Ph 3 Bi (2.2 eq., 41.26 g, Aldrich), Cu(OAc), (2.0 eq., 15.48 g, Aldrich), Et 3 N (2.0 eq., 8.62 g) in CHCl, (100 mL) was stirred under N 2 at room temperature for 6 days (monitoring by TLC). The solids were removed by filtration through a plug of Celite rinsing with CHCl,/MeOH (3x75 mL). The filtrate was concentrated, dissolved in hot
CH
2 CI2/MeOH and filtered through a large plug of silica gel eluting with CHC12/MeOH 2L). The filtrate was concentrated and the residue purified by flash chromatography eluting with straight CH 2 C1 2 gradient to CH,C1 2 /MeOH 2,4-Dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro- 1 crystallized during concentration of the fractions containing the product, and was isolated by filtration as a white solid.
Step B: Synthesis of 3-Azido-2,4-dioxo-l,5-bis-phenyl-2,3,4,5tetrahydro-1H-1,5-benzodiazepine For this substrate, General Procedure 8-K was modified in the following manner. Initially the product from Step A was suspended (not a solution) in THF at -70 0 C, and following addition of the KN(TMS), solution, this suspension was allowed to warm to -20 0 C over a period of 10 minutes, durihg which the suspension became a solution, and was re-cooled to -70 0 C; then treated as described in the general procedure. The title compound was purified by trituration with hot CHCl 3 /hexanes to yield 3-azido-2,4-dioxo-1,5-bisphenyl-2,3,4,5-tetrahydro-1H- ,5-benzodiazepine as a white solid.
WO 98/28268 PCT/US97/22986 363 Step Synthesis of 3-Amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5tetrahydro-1H-1 Following General Procedure 8-L using the product from Step B, 3-amnino- 2,4-dioxo- 1,5-bis-phenyl-2,3 ,4,5-tetrahydro- 1H-i ,5-benzodiazepine was prepared as a white solid. Purification was by flash chromatography eluting with
CH,CI
2 IMeOH (98:2 gradient to 95:5, with 5% NH 3 in the MeOH).
Step2 D: Synthesis of 3-[N'-QI-Butoxycarbonyl)-L-alaninyl] -arnino- 2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-.1H.1 benzodiazepine Following General Procedure I above using N-Boc-L-alanine (Novabiochem) and the product from Step C, 3-[N'-(t-butoxycarbonyl)-Lalaninyl]-amino-2,4-dioxo- 1,5-bis-phenyl-2,3,4,5-tetrahydro- 1H- benzodiazepine was prepared as a white foam. Purification was by flash chromatography eluting with CH 2 Cl,/EtOAc (4:1 gradient to 3:1).
Step E: Synthesis of 3-(L-Alaninyl)-amino-2,4-dioxo-1,5-bisphenyl-2,3,4,5-tetrahydro-i H-i Hydrochloride Following General Procedure 8-N above using the product from Step D, the title compound was prepared as a white amorphous solid.
Example 8-X Synthesis of 3-Amino-2,3-dihydro-1-methyl-5-pheny-1H-1 ,4-benzodiazepin-2-one Following the method of R. G. Sherrill et al., J. Org. Chem., 1995, 60, 730- 734 and using glacial acetic acid and HBr gas, the title compound was prepared.
Example 8-Y Synthesis of 3-(L-Valinyl)-amino-2,3-dihydro-l-methyl- 5-phenyl-1 H-1,4-benzodiazepin-2-one Step A Synthesis of 3- [N'-(tert-Butylcarbamate)-L-valinylI -amino- 2,3-dihydro-1 -methyl-5-phenyl-1 H-i ,4-benzodiazepin-2-one WO 98nM68 WO 9828268PCT/US97/22986 364 (S)-3-Amino- I ,3-dihydro- I -methyl-5-phenyl-2H- I ,4-benzodiazepin-2-one, (1 S)-7,7-dimethyl-2-oxobicyclo[2.2. 1 heptane-l1-methanesulfonate (Example 8-B, Step A) was free based by partitioning between methylene chloride and I M potassium carbonate. The free amine was then coupled with N-Boc-valine following General Procedure D to give the title compound.
C-,
6
H
32
N
4 0 4 (MW 464.62); mass spectroscopy 464.3.
Anal. Calcd for C2 6
H
32
N
4 0 4 C, 67.2-2; H, 6.94; N, 12.06. Found: C, 67.29; H, 6.79; N, 11.20.
SteR B Synthesis of 3-(L-valinyl)-amino-2,3-dihydro-1-methyl-5phenyl-1H-1 ,4-benzodiazepin-2-one Following General Procedure 8-C and using 3-[N'-(teri'-butylcarbamate)-Lalaninyl]-amino-2,3-dihydro- 1 -methyl-5-phenyl- I H-i ,4-benzodiazepine-2-one, the title compound was prepared as a white foam.
C
2
,H
23
N
4 0 2 (MW 363.48); mass spectroscopy 364.2.
Example 8-Z Synthesis of 3-(L-tert-Leucinyl)-amino-2,3-dihydro-1-methyl- 5-phenyl-1H-1,4-benzodiazepin-2-one Step A Synthesis of 3-[N'-(tert-Butylcarbamate)-L-tert-leucinyllamino-2,3-dihydro-1-methyl-5-phenyl-l1H-i ,4benzodiazepin-2-one -amino- I ,3-dihydro- 1 -methyl-5 -phenyl-2H- 1 ,4-benzodiazepin-2-one, (1 S)-7,7-dimethyl-2-oxobicyclo[2.2.1I]heptane-lI-methanesulfonate (Example 8-B, Step A) was free based by. partitioning between methylene chloride and I M potassium carbonate. The free amine was then coupled with N-Boc-tert-leucine following General Procedure D to give the title compound.
C2 7
H
35
N
4 0 4 (MW 479.66); mass spectroscopy 479.
Step B Synthesis of 3-(L-tert-Leucinyl)-amino-2,3-dihydro-1methyl-5-phenyl-1 H-i ,4-benzodiazepin-2-one WO 98/28268 WO 9828268PCTIUS97/22986 365 Following General Procedure 8-C and using -(tert-butylcarbamate)-Ltert-leucinyl]-amino-2,3-dihydro- 1 -methyl-5-phenyl- 1 H-i ,4-benzodiazepine-2one, the title compound was prepared as a white foam.
Anal. Calcd for C, 22
H
2 5
N
4 C, 68.19; H, 7.02; N, 14.40. Found: C, 68.24; H, 7.00; N, 14.00.
Example 8-AA Synthesis of 3-(L-Alaninyl)-amino-2,3-dihydro-1 IH-1 ,4-benzodiazepine 2,3-Dihydro- 1,5-dimethyl- 1H-I ,4-benzodiazepine was prepared following General Procedures 8-1 (using methyl iodide), 8-D and 8-F. Coupling of this intermediate with Boc-L-alanine (Novo) using General Procedure D, followed by deprotection using General Procedure 5-B3 afforded the title compound which was used without further purification.
Example 8-AB Synthesis of 3-(L-3-Thienylglycinyl)amino-2,4-dioxo- 1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro- 1H-1 Step A: Synthesis of N-(t-Butoxycarbonyl)-L-3-thienylglycine N-(t-Butoxycarbonyl)-L-3-thienylglycine was prepared from L-cc-(3thienyl)glycine (Sigma) by the procedure described in Bodansky, M. et al; The Practice of Peptide Synthesis; Springer Verlag; 1994, p. 17.
Step2 B: Synthesis of 3-[N'-(t-Butoxycarbonyl)-L-3-thienylglycinyljamino-2,4-dioxo-1 ,5-bis-(2,2-dimethylpropyl)-2,3,4,5tetrahydro-l H-i Following General Procedure D above using the product from Example 8-V, Step C and the product from Step A above, 3-[N'-(t-butoxycarbonyl)-L-3thienylglycinyl]-amino-2,4-dioxo- 1 ,5-bis-(2,2-dimethylpropyl)-2,3 1 H-i ,5-benzodiazepine was prepared.
WO 98128268 PCTIUS97/22986 366-- Step Synthesis of 3-(L-3-Thienylglycinyl)amino-2,4-dioxo-1,sbis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro..1H-i,5benzodiazepine Following General Procedure 8-N above using the product from Step B, the title compound was prepared.
Example 8-1 Synthesis of 3-(3,5-Difluorophenylacetyl)amino- 2,3-dihydro-1 -methyl-5-phenyl-1H- 1,4-benzodiazepin-2-one Following General Procedure A above using 3,5-difluorophenylacetic acid (Oakwood) and 3-amino-2,3-dihydro-l1-methyl-5-phenyl- IH-I ,4-benzodiazepin-2one (Example the title compound was prepared as a solid having a melting point of 236-239*C. The reaction was monitored by tic on silica gel (Rf 0.7 in 10% methanol/dichloromethane) and purification was by silica gel chromatography using 10% methanol/dichloromethane as the eluant.
NMR data was as follows: 'H-nmr (CDCI 3 6 7.4 (in, 9H), 6.90 (dd, J 6.0, 2.2, 2H), 6.73 (dt, J 6.6, 2.2, 2.2, 6.6, 1H), 5.50 J 7.7, 111), 3.68 2H), 3.46 3H1).
3 C-nmr (CDCl 3 6 172.9, 165.2, 163.5, 138.3, 133.6, 127.7, 126.4, 125.4, 124.6, 123.9, 120.3, 117.2, 108.2, 107.9, 98.4, 62.8, 38.6, 30.9.
C
24 HjqN 3 0 2 F (MW 419); mass spectroscopy (MHW) 420.
Example 8-2 Synthesis of 3-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)ainino- 2,3-dihydro-1-ethyl-5-phenyl-1H-1 ,4-benzodiazepin-2-one Following General Procedure A above using L-alanine (Example B) and 3-amino-2 ,3-dihydro- 1-ethyl-5-phenyl- 1H- 1,4benzodiazepin-2-one (prepared as described in Example 8-X using ethyl iodide), the title compound was prepared as a solid having a melting point of 155- 158'C. The reaction was monitored by tic on silica gel (Rf 0.48 in methanol/dichloromethane) and purification was by silica gel chromatography WO 98/28268 WO 9828268PCT[US97/22986 367 using 10% methanol/dichioromethane as the eluant, followed by recrystallization from diethyl ether.
NMR data was as follows: 'H-nr (CDCl 3 5 7/73 J 7.7, 1H), 7.4 (in, 9H), 6.86 (in, 2H), 6.68 (in, 1H1), 6.58 J 1H), 5.43 (dd, J 2.7, 4.9, 2.7, 1H), 4.67 (in, 1H), 4.3 (in, 1H), 3.7 (in, 1H), 3,52 2H), 1.46 (dd, J 6.6, 6.6, 3H), 1. 10 (dt, J 7.1, 1.1, 6.0, 3H).
3 C-nmr (CDC 3 6 167.8, 164.8, 163.4, 161.3, 136.7, 133.6, 127.6, 126.4, 125.2, 124.0, 118.1, 107.8, 98.3, 9S.5, 62.9, 44.7, 38.6, 14.5, 8.7.
C
28
H
26
N
4 0 3
F
2 (MW 504); mass spectroscopy (MH 505.
Example 8-3 Synthesis of 3-[N'-(3,5-Difluorophenylacetyl)-L-alaninylj-amino- 2,3-dihydro-5-phenyl-1H-1 ,4-benzodiazepin-2-one Following General Procedure D above using N-(3 L-alanine (Example B) and 3-amino-i, 3-dihydro-5-phenyl-2H- 1,4benzodiazepin-2-one (GAS: 103343-47-1. Sherrill, R. Sugg, E. E. J. Org.
Chem. 1995, 60, 730.), the title compound was prepared as a white solid.
Purification was by trituration with 1: 1 ether/hexanes.
C
26
H
2 jF 2
N
4 0 3 (MW 475.51); mass spectroscopy 476.
Anal. Calcd for C 26
H
2
,F
2
N
4 0 3 C, 65.54; H, 4.65; N, 11.76. Found: C, 65.37; H, 4.67; N, 11.63.
Example 8-4 Synthesis of 3-[N'-(3,5-Difluorophenylacetyl)-L-alaninylj-amino- 2,3-dihydro-1-methyl-5-(1-piperidinyl)- 1H-1 ,4-benzodiazepin-2-one Following General Procedure D above using L-alanine (Example B) and 3-amino-i ,3-dihydro-1-inethyl-5-(1-piperidinyl)-2H- 1 ,4-benzodiazepin-2-one (Example the title compound was prepared as a white solid having a melting point of 154-160*C.
C
26
H
29
FN
5 0 3 (MW =497.60); mass spectroscopy 497.
WO 98/28268 PCT[US97/22986 368 Anal. Calcd for C 2
H
29 F7 2
N
5 0 3 C, 62.75; H, 5.89; N, 14.08. Found: C, 62.52; H, 5.81; N, 13.62.
Example Synthesis of 3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino-7-chloro- 2,3-dihydro-1-methyl-5-phenyl-1H- 1,4-benzodiazepin-2-one Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)-amino-7-chloro-2 ,3-dihydro- 1methyl-5-phenyl-1H-1 ,4-benzodiazepin-2-one (Example the title compound was prepared as a white solid having a melting point of 126.5- 1300C.
C
27
H
23 C1F 2
N
4 0 3 (MW 524. mass spectroscopy 523.7.
Anal. calcd for C 27
H
23 C1F 2
N
4 0 3 C, 61.78; H, 4.42; N, 10.67. Found: C, 61.92; H, 4.52; N, 10.46.
Example 8-6 Synthesis of 3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino-7-bromo- 2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1 ,4-benzodiazepin-2-one Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)-amino-7-bromo-2 ,3-dihydro- 1methyl-5-(2-fluorophenyl)-1H-1 ,4-benzodiazepin-2-one (Example the title compound was prepared as a white solid.
C
27
H
22 BrF 3
N
4
O
3 (MW 587.43); mass spectroscopy 587.
Anal calcd for C 27
H
22 BrF 3
N
4
O
3 C, 55.21; H, 3.78; N, 9.54. Found: C, 55.25; H, 4.00; N, 9.72.
Example 8-7 Synthesis of 3-IIN'-(3,5-Difluorophenylacetyl)-N' -methyl-L-alaninyl]-amino- 2,3-dihydro-1-methyl-5-phenyl- 1H-1 ,4-benzodiazepin-2-one WO 98/28268 PTU9128 PCTIUS97/22986 369 Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(N '-methyl-L-alaninyl)-amino-2 ,3-dihydro- 1methyl-5-phenyl-l1H-i ,4-benzodiazepin-2-one (Example the title compound was prepared as a white solid.
1H NMR (300 MHz, CDCl 3 6 7.65 (1H, d, J=7.9 Hz), 7.59-7.34 (8H1, in), 7.23 (1H1, t, J=7.2 Hz), 6.84 (2H1, d, J=6.0 Hz), 6.65 (1H1, t, J=7.2 Hz), 5.46 (1H, d, J=7.9 Hz), 5.42 (L11, d, J=7.2 Hz), 3.78 (2H1, 3.47 (3H, 3.02 (3H1, 1.42 (3H, d, J=7.1 Hz).
C
28
H
26
F
2
N
4 0 3 (MW =505.205 mass spectroscopy 505.2046.
Example 8-8 Synthesis of 3-IIN'-(3,5-Difluorophenylacetyl)-L-alaninylj-amino-7-chloro- 2,3-dihydro-1-methyl-5-(2-chlorophenyl)-1H-1 ,4-benzodiazepin-2-one Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)-amino-7-chloro-2 ,3-dihydro- 1methyl-5-(2-chlorophenyl)- 1H- 1,4-benzodiazepin-2-one .(Example the title compound was prepared as a white solid.
C
27
H
22 C1 2
F
2
N
4 0 3 (MW 559.43); mass spectroscopy 559.2.
Anal. calcd for C 27 H1 22
C
2 FAN0 3 C, 57.97; H, 3.96; N, 10.02. Found: C, 57.99; H, 3.98; N, 9.92.
Example 8-9 Synthesis of 3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino-5-cyclohexyl- 2,3-dihydro-1-methyl-1H-1 ,4-benzodiazepin-2-one Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)-amino-5-cylcohexyl-2 ,3-dihydro- 1methyl-lH-1,4-benzodiazepin-2-one (Example the title compound was prepared as a white solid.
C
27
H
30
F
2
N
4 0 3 (MW 497.2364); mass spectroscopy 497.2370.
WO 98/28268 PCTUS97/22986 370 Example 8-10 Synthesis of 3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino- 2,3-dihydro-1-methyl-7-nitro-5-phenyl- 1H-1,4-benzodiazepin-2-one Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)-amino-2 ,3-dihydro-l1-methyl-7nitro-5-phenyl-1H-1 ,4-benzodiazepin-2-one (Example the title compound was prepared as a yellow solid.
'H NMR (300 MHz, CDCl 3 6 8.44 (1 H, dd, J 9. 0 Hz), 8.42 (1H, dd, J=2.3, 9.0 Hz), 8.23 (2H1, d, J=2.6 Hz), 7.73 (2H1, in), 7.56-7.40 (12H, in), 6.83 (4H, mn), 6.69 (2H1, in), 6.37 (2H1, apt, J=7.8 Hz), 5.45 (1H, d, J=7.7 Hz), 5.44 (1H1, d, J=7.7 4.71 (2H, in), 3.56 (2H, 3.55 (2H1, 3.52 (3H, 3.51 (3H, 1.47 d, J=7.0 Hz), 1.46 (3H, d, Hz).
C
27 H2 3
F,N
5 0 5 (M +H 536.1747); mass spectroscopy found 536.1749.
Example 8-11 Synthesis of 3-[N'-(3,5-Difluorophenylacetyl)-L-alaninylj-amino- 2,3-dihydro-l-methyl-5-(2-fluorophenyl)- 1H-1 ,4-benzodiazepin-2-one Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)-amino-2, 3-dihydro-l1-methyl-5-(2fluorophenyl)-1H-1 ,4-benzodiazepin-2-one (Example 84I), the title compound was prepared as a white solid having a melting point of 185-188'C.
C
27
H
23
F
3
N
4 0 3 (MW 508.54); mass spectroscopy found (M H) 509.3.
Anal. calcd for C 27
H
23
F
3
N
4 0 3 C, 63.78; H, 4.53; N, 11.02. Found: C, 63.99; H, 4.49; N, 10.84.
Example 8-12 Synthesis of 3-[N'-(3,5-Difluorophenyl-ci-hydroxyacetyl)-L-valinyl]-amino- 2,3-dihydro-1-methyl-5-phenyl-lH- 1,4-benzodiazepin-2-one WO 98/28268 PCT/US97/22986 371 Following General Procedure D above using acid (Example L) and 3-(L-valinyl)-amino-2 ,3-dihydro-l1-methyl-5-l1H- 1,4benzodiazepin-2-one (Example the title compound was prepared as a white solid.
C
29
H
28
F
2
N
4 0 4 (MW 534.61); mass spectroscopy found 535.3.
Anal. calcd for C 29 11 28
F
2
N
4 0 4 C, 65.16; H, 5.28; N, 10.48. Found: C, 65.34; H, 5.43; N, 10.35.
Example 8-13 Synthesis of 3-[N'-(3,5-Difluoropheny-r-hydroxyacety)-L-tert-leucinyll-amiino- 2,3-dihydro- 1-methyl-5-phenyl-1H-1 ,4-benzodiazepin-2-one Following General Procedure D above using acid (Example L) and 3-(tert-leucinyl)-amino-2 ,3-dihydro-l1-methyl-5- 1H- 1,4benzodiazepin-2-one (Example the title compound was prepared as a white solid.
C
30
H
30
F
2
N
4 0 4 (MW 548.64); mass spectroscopy found (M 549.3.
Anal. calcd for C 30
H
30
F
2
N
4 0 4 C, 65.68; H, 5.5 1; N, 10. 21. Found: C, 65.38; H, 5.44; N, 10. 14.
Example 8-14 Synthesis of 3-IjN'-(3,5-Difluorophenylacetyl)-L-alaninylJ-amino- 2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-1 ,4-benzodiazepin-2-one Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)-amino-2 ,3-dihydro-l1-methyl-5-(3fluorophenyl)-1H-1 ,4-benzodiazepin-2-one (Example the title compound was prepared as an off white solid.
C
27
H
23
F
3
N
4 0 3 (MW 508.50); mass spectroscopy found 509.3.
'H NMR (300 MHz, CDC1 3 6 7.65-7.53 (4H, in), 7.42-7.24 (12H, in).
7.22-7.14 (2H, in), 6.87-6.81 in), 6.75-6.65 (2H1, in), 6.29 (111, d, J=6.6 Hz), 6.21 (1H, d, J=7.2 Hz), 5.45 (1H, d, J=7.8 Hz), 5.44 (LH, d, WO 98/28268 PCTIUS97/22986 372 Hz), 4.67 (211, in), 3.57 (2H, 3.55 (211, 3.474 (3H, 3.468 (3H, s), 1.48 (3H1, d, J=7.2 Hz), 1.47 d, J=6.8 Hz).
Example 8-15 Synthesis of 3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl~amino- 2,3-dihydro-1-methyl-5-(4-fluorophenyl)-1H-1 ,4-benzodiazepin-2-one Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)-amino-2 ,3-dihydro-l1-methyl-5-(4fluorophenyl)-1H-1 ,4-benzodiazepin-2-one (Example the title compound was prepared as an off-white solid.
C
27
H
23
F
3
N
4 0 3 (MW 508.50); mass spectroscopy found 509.7.
Anal. calcd for C 27
H
23
F
3
N
4 0 3 C, 63.78; H, 4.56; N, 11.01. Found: C, 64.09; H, 4.81; N, 10.40.
Example 8-16 Synthesis of 3-[N'-(Cyclopentyl-c!-hydroxyacetyl)-L-alaninyl]-anmino- 2,3-dihydro-1-methyl-5-phenyl-1H-1 ,4-benzodiazepin-2-one Following General Procedure D above using )-a-hydroxycyclopentylacetic acid (Example P) and 3-(L-alaninyl)-amino-2,3-dihydro-1methyl-5-1H-1 ,4-benzodiazepin-2-one (Example the title compound was prepared as a white solid.
Isomer 1:
C
26
H
30
N
4 0 4 (MW 462.60); mass spectroscopy found (M 463.6.
Anal. calcd for C 26
H-
30
N
4 0 4 C, 67.5 1; H, 6.54; N, 12. 11. Found: C, 67.78; H, 6.65; N, 12.29.
Isomer 2:
C
26
H
30
N
4 0 4 (MW 462.60); mass spectroscopy found 463.4.
Anal. calcd for C 26
H
30
N
4 0 4 C, 67.5 1; H, 6.54; N, 12.11. Found: C, 67.74; H, 6.56; N, 11.81.
WO 98/28268 PCTIUS97/22986 -373 Example 8-17 Synthesis of 3-[N'-(Cyclopentyl-ot-hydroxyacetyl)-L-valinyl]-amino- 2 ,3-dihydro-1-methyl-5-phenyl-1H-1 ,4-benzodiazepin-2-one Following General Procedure D above using (±)-a-hydroxycyclopentylacetic acid (Example P) and 3-(L-valinyl)-amino-2,3-dihydro-1methyl-5-1H-1,4-benzodiazepin-2-one (Example the title compound was prepared as a white solid.
Isomer 1:
C
28
H
34
N
4 0 4 (MW 490.66); mass spectroscopy found (M 491.4.
Isomer 2:
C
28
H
34
N
4 0 4 (MW 490.66); mass spectroscopy found 491.4.
Example 8-18 Synthesis of 3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyljamino- 2,3-dihydro-1 ,5-dimethyl-1H-1 ,4-benzodiazepin-2-one Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)-amino-2,3-dihydro-1 1H-1 ,4-benzodiazepin-2-one (Example 8-AA), the title compound was prepared as a solid (mp. 222-223*C). The product was purified by slurrying in ether.
MW 429; mass spectroscopy found (M 429.
Anal. calcd: C, 61.67; H, 5.18; N, 13.08. Found: C, 61.43; H, 5.17; N, 12.79.
Example 8-19 Synthesis of 3-IIN'-(3,5-Difluorophenylacetyl)-L-alaninyllamino- 2,3-dihydro-l-isobutyl-5-phenyl)-1H-1 ,4-benzodiazepin-2-one Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)-amino-2 ,3-dihydro- phenyl-1H-1 ,4-benzodiazepin-2-one (Example the title compound was WO 98/28268 PCT1US97t22986 374 prepared as a solid (mp. 210-211 VC). The product was purified by tiruration from ether/hexanes.
C
30
H
3
OF
2
N
4 0 3 (MW =532.23); mass spectroscopy found 532.
Anal. calcd: C, 67.66; H, 5.68; N, 10.52. Found: C, 67.67; H, 5.55; N, 10.34.
Purification by C 2000 chromatography, eluting with hexanes/ethyl acetate (20:80) afforded the following isomers: Isomer 1: Melting Point: 202-203*C.
C
3 0H 3
OF
2
N
4 0 3 (MW 532.23); mass spectroscopy found 532.23.
Isomer 2: Melting Point: 211-212'C.
C
30
H
3
OF
2
N
4 0 3 (MW 532.23); mass spectroscopy found 532.
Example 8-20 Synthesis of 3-[N'-(3,5-Difluorophenyl-a-hydroxyacetyl)-L-alaninyl] amino- 2,3-dihydro-1-methyl-5-phenyl-1H- 1,4-benzodiazepin-2-one Following General Procedure D above using 3,5-difluoromandelic acid (Fluorochem) and 3-(L-alaninyl)amino-2 ,3-dihydro-l1-methyl-5-phenyl-l1H- 1,4benzodiazepin-2-one (Example the title compound was prepared as a solid. The product was purified by LC 2000 chromatography, eluting with hexanes/ethyl acetate (20:80).
Isomer 1: Melting Point: 240-24 1 C.
C
27
H
24
F
2
N
4 0 4 (MW 506.51); mass spectroscopy found (M 506.
Anal. calcd for C2 7
H
24
F
3
N
4 0 4 C, 64.03; H, 4.78; N, 11.06. Found: C, 64.31; H, 4.86; N, 11.04.
C Isomer 2: Melting Point: 128*C.
C
27
H
24
F
2
N
4 0 4 (MW 506.51); mass spectroscopy found 506.
WO 98/28268 WO 9828268PCT/US97/22986 375 Anal. calcd for C 27
H
2
,F
3
N
4 0 4 C, 64.03; H, 4.78; N, 11.06. Found: C, 63.92; H, 5.00; N, 10.88.
Example 8-21 Synthesis of 3-[N'-(3,5-Difluorophenyl-a-oxoacetyl)-L-alaninyllamino- 2,3-dihydro-1-methyl-5-phenyl-1H-1 ,4-benzodiazepin-2-one Following General Procedure D above using 3,5-difluoro-ce-oxoacetic acid (Example 0) and 3-(L-alaninyl)amino-2 ,3-dihydro-l1-methyl-5-phenyl- 1H- 1,4benzodiazepin-2-one (Example the title compound was prepared as a solid (mp. 128-129*C). The product was purified by LC 2000 chromatography, eluting with hexanes/ethyl acetate (30:70).
C
27
H
22
F
2
N
4 0 4 (MW 504); mass spectroscopy found 503.9.
Optical Rotation: [at] -113.64 589; -333.33 365 (c 1, MeOH).
Anal. calcd for C 27
H
22
F
3
N
4 0 4 C, 64.28; H, 4.40; N, 11. 11. Found: C, 64.51; H, 4.54; N, 11.04.
Example 8-22 Synthesis of 3-IIN'-(2-Methylthioacetyl)-L-alaninyl]amino- 2,3-dihydro-1-methyl-5-phenyl-1H-1 ,4-benzodiazepin-2-one Following General Procedure D above using 2-methylthioacetic acid (Aldrich) and 3-(L-alaninyl)-amino-2 ,3-dihydro-l1-methyl-5-phenyl-l1H- 1,4benzodiazepin-2-one (Example the title compound was prepared as a solid (mp. 205-206*C). The product was purified by slurrying in hexanes/ether
C
22
H
24
N
4 0 3 S (MW 424); mass spectroscopy found 424.
Anal. calcd for C 22
H
24
N
4 0 3 S: C, 62.25; H, 5.70; N, 13.20. Found: C, 62.11; H, 5.89; N, 13.02.
WO 98/28268 WO 9828268PCTIUS97/22986 376 Example 8-23 Synthesis of 3-[N'-(3,5-Difluorophenylacetyl)-L-valinyl]amino- 2,3-dihydro-l-methyl-5-phenyl-1H-1 ,4-benzodiazepin-2-one Following General Procedure D above using 3 ,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-valinyl)amino-2,3-dihydro-l1-methyl-5phenyl-1H-1 ,4-benzodiazepin-2-one (Example the title compound was prepared as a solid (mp. 228-229'C). The product was purified by slurrying in ether/hexanes (80:20).
C
29
H
28
F
2
N
4 0 3 (MW 518); mass spectroscopy found (M 518.
Optical Rotation: -117.96 589; -341.55 365 (c 1, MeOH).
Anal. calcd for C 29
H-
28 FAN0 3 C, 67.17; H, 5.44; N, 10. 8. Found: C, 67.45; H, 5.49; N, 10. 61.
Example 8-24 Synthesis of 3-IIN'-(3,5-Difluorophenylacetyl)-L-tert-Ieucinyl]amino- 2,3-dihydro-1-methyl-5-phenyl-1H-1 ,4-benzodiazepin-2-one Following General Procedure D above using 3 ,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-tert-leucinyl)amino-2 ,3-dihydro-l1-methyl-5phenyl-1H-1 ,4-benzodiazepin-2-one (Example the title compound was prepared as a solid (mp. 221-222'C). The product was purified by slurrying in ether.
Q
30
H
30
F
2
N
4 0 3 (MW 532); mass spectroscopy found 532.
Anal. calcd for C 30
H
30
F
2
N
4 0 3 C, 67.66; H, 5.68; N, 10.52. Found: C, 67.93; H, 5.95; N, 10.25.
Example 8-25 Synthesis of 3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyllamino- 2,3-dihydro-1-isopropyl-5-phenyl-1H-1 ,4-benzodiazepin-2-one Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)aniino-2 ,3-dihydro-l1-isopropyl-5- WO 98/28268 PCT/US97/22986 377 phenyl-1H-1 ,4-benzodiazepin-2-one (Example the title compound was prepared as a solid (mp. 208-209*C). The product was purified by slurrying in ether/hexanes 1).
MW 518; mass spectroscopy f ound 518.
Anal. calcd: C, 67.17; H, 5.44; N, 10.80. Found: C, 67.39; H, 5.62; N, 10. 84.
Example 8-26 Synthesis of 3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyllamino- 2,3-dihydro-l-cyclopropylmethyl-5-phenyl-1H-1,4-benzodiazepin-2-one Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)amino-2 ,3-dihydro- 1- 1H- 1,4-benzodiazepin-2-one (Example the title compound was prepared as a solid (mp. 203-205*C). The product was purified by slurrying in ether/hexanes.
C
30
H
28
F
2
N
4 0 3 (MW 530.58); mass spectroscopy found 530.
Anal. calcd for C 30 H1 2
AFN
4 0 3 C, 67.91; H, 5.32; N, 10.56. Found: C, 68.14; H, 5.54; N, 10.62.
Example 8-27 Synthesis of 3-[N'-(3,5-Difluorophenyl-oi-luoroacetyl)-L-alaninyllamiino- 2,3-dihydro-1-methyl-5-phenyl-1H-1 ,4-benzodiazepin-2-one Following General Procedure D above using fluoroacetic acid (Example S) and 3-(L-alaninyl)amino-2 ,3-dihydro-l1-methyl-5phenyl-1H-1,4-benzodiazepin-2-one (Example the title compound was prepared as a solid. The product was purified by LC 2000 chromatography, eluting with hexanes/ethyl acetate (35:65).
Isomer 1: Melting Point: 119-120 0
C.
C
27
H,
3
F
3
N
4 0 3 (MW 508); mass spectroscopy found (M 508.
Optical Rotation: [cj] -115.62 589; -292.09 365 (c 1, MeOH).
WO 98/28268 PCT1US97/22986 378 Anal. calcd for C 2 7
H-
23 FAN0 3 C, 62.66; H, 4.67; N, 10. 82. Found: C, 62.55; H, 4.74; N, 10.51.
Isomer 2: Melting Point: 198-199*C.
C
27
H
2 3
F
3
N
4 0 3 (MW 508); mass spectroscopy found 508.
Optical Rotation: -99.65 589; -279.72 365 (c 1, MeOH).
Anal. calcd for C 27
H
23
F
3
N
4 0 3 C, 62.66; H, 4.67; N, 10.82. Found: C, 62.40; H, 4.62; N, 10.84.
Examples 8-28 to 8-139 By following the procedures set forth above, the following additional compounds were prepared: 8-28 8-29 8-30 8-31 8-32 8-33 8-34 8-35 ,5-difluorophenylacetyl)-L-alaninyl] amino-2 ,3dihydro-l1-n-propyl-5-phenyl- 1H- 1,4-benzodiazepin-2-one -(3-methylbutyryl)-L-phenylglycinyllamino-2 ,3-dihydro- 1-methyl-S -phenyl- 1H- 1,4-benzodiazepin-2-one 3-[N ,5-difluorophenylacetyl)-L-phenylglycinyl]amino-2 .3dihydro-l1-methyl-5-phenyl-l1H-i ,4-benzodiazepin-2-one -(2-phenylthioacetyl)-L-alaninyll amino-2, 3-dihydro- 1- 1H- 1,4-benzodiazepin-2-one -(3-methylbutyryl)-L-alaninyllamino-2 ,3-dihydro- 1methyl-S -phenyl- 1H- 1,4-benzodiazepin-2-one 3-[N '-(2-phenylthioacetyl)-L-phenylglycinyljamino-2 .3dihydro-l1-methyl-S -phenyl- 1H- 1,4-benzodiazepin-2-one 3-[N '-(3-(4-methoxyphenyl)propionyl)-L-alaninylamino-2 .3- 1H-1 ,4-benzodiazepin-2-one -(3-bromophenylacetyl)-L-alaninyllamino-2 ,3-dihydro- 1 1H- 1,4-benzodiazepin-2-one -(4-cyclohexylbutyryl)-L-alaninyl] amino-2 ,3-dihydro- 1 111- 1 ,4-benzodiazepin-2-one 8-36 WO 98/28268 PCTIUS97/22986 379 8-37 8-38 8-39 8-40 8-41 8-42 8-43 8-44 8-45 8-46 3- [N '-(4-methoxyphenylacetyl)-L-alaninyllamino-2 ,3-dihydro- 1i-methyl-5-(2-pyridyl)-1H- 1 ,4-benzodiazepin-2-one 3 -[N'-(3-methyl-2-hydroxylbutyryl)-L-alaninylj amino-2 .3dihydro- 1 -methyl-5-phenyl- 1 H-i ,4-benzodiazepin-2-one 3-[N '-(3-methyl-2-hydroxylbutyryl)-L-alaninyl]amino-2 ,3dihydro-l1-methyl-5-phenyl-l1H-i ,4-benzodiazepin-2-one 3-[N 3-dimethylbutyry1)-L-alaniny11amino-2 ,3-dihydro- 1- 1H- 1,4-benzodiazepin-2-one 3-[N '-(thien-2-yl-acetyl)-L-alaninyl]amino-2 ,3-dihydro- 1methyl-5-(2-pyridyl)- 1H- 1,4-benzodiazepin-2-one ,5-difluorophenylacetyl)-L-alaninyl]amino-2 ,3dihydro-l1-methyl-5-(2-pyridyl)-1H- 1,4-benzodiazepin-2-one 3-[N '-(3-bromophenylacetyl)-L-alaninyl]amino-2 ,3-dihydro- 1methyl-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3-[N '-(2-phenylthioacetyl)-L-alaninyl]amino-2 ,3-dihydro- 1methyl-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3-[N'-(4-ethoxyphenylacetyl)-L-alaninyllamino-2 ,3-dihydro- 1 -methyl-5-(2-pyridyl)- 1H- 1 ,4-benzodiazepin-2-one 3-[N '-(4-trifluoromethylphenylacetyl)-L-alaninyl]axnino-2 .3dihydro-l1-methyl-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3- [N -di(trifluoromethyl)phenylacetyl)-L-alaninylI amino- 2,3-dihydro- 1 -methyl-5-(2-pyridyl)- 1H- 1 ,4-benzodiazepin-2one 3-[N '-(2-methylthioacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1methyl-5-(2-pyridyl)- 1H- 1,4-benzodiazepin-2-one -(2-cyclohexylacetyl)-L-alaninyl] amino-2 ,3-dihydro- 1methyl-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3-[N ,6-pentafluorophenyloxyacetyl)-Lalaninyl]amino-2 ,3-dihydro- 1 -methyl-5-(2-pyridyl)- 1 H- 1,4benzodiazepin-2-one 3- -(thionaphth-3-ylacetyl)-L-alaninyl]amino-2 ,3-dihydro- 1 niethyl-5-(2-pyridyl)- IH-1 ,4-benzodiazepin-2-one 8-47 8-48 8-49 8-50 8-51 WO 98/28268 PTU9t28 380 8-52 6-trixnethylphenylacetyl)-L-alaninyljamino-2 ,3dihydro-l1-methyl-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 8-53 3-[N '-((4-phenyl)phenylacetyl)-L-alaninyl] amino-2 ,3-dihydro- 1 -methyl-5-(2-pyridyl)- 1H- 1,4-benzodiazepin-2-one 8-54 3-[N ,4-difluorophenylacetyl)-L-alaninyljamino-2 ,3dihydro-l1-methyl-5-(2-pyridyl)- 1H- 1,4-benzodiazepin-2-one 8-55 3-[N '-(4-(thien-2-yl)butyryl)-L-alaninyl]amino-2 ,3-dihydro- 1methyl-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 8-56 3-[N '-(5-methylhexanoyl)-L-alaninyl] amino-2 ,3-dihydro- 1methyl-5-(2-pyridyl)- 1H- 1,4-benzodiazepin-2-one 8-57 3-[N '-(2-methoxycarbonylacetyl)-L-alaninyl]amino-2 ,3dihydro-l1-methyl-5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2-one 8-60 ,6-difluorophenyl)-ca-hydroxyacetyl)-Lalaninyljamino-2 ,3-dihydro- 1 -methyl-5-(2-pyridyl)- 1 H- 1,4benzodiazepin-2-one 8-61 3-[N '-(4-fluorophenyl)-ca-hydroxyacetyl)-L-alaninylj'amino- 2, 3-dihydro-l1-methyl-5-(2-pyridyl)- 1H- 1,4-benzodiazepin-2one 8-62 alaninyl]amino-2 ,3-dihydro-l1-methyl-5-(2-pyridyl)-l1H- 1,4benzodiazepin-2-one 8-63 3-[N ,4,6-trifluoropheny 1)acetyl)-L-alaninyl] amino-2 ,3dihydro-1-methyl-5-(2-pyridyl)- lH-1 ,4-benzodiazepin-2-one 8-64 3-[N '-(2-trifluoromethyl-4-fluorophenyl)acetyl)-Lalaninyl]amino-2 ,3-dihydro-l1-methyl-5-(2-pyridyl)-l1H- 1,4benzodiazepin-2-one 8-65 3- -(4,4,4-trifluorobutyryl)-L-alaninyl]amino-2 ,3-dihydro- 1 -methyl-5-(2-pyridyl)- 1H- 1 ,4-benzodiazepin-2-one 8-66 3-[N '-(4-iso-propylphenylacetyl)-L-alaninyllamino-2, 3dihydro-l1-methyl-5-(2-pyridyl)- 1H- 1,4-benzodiazepin-2-one 8-67 3- -(3-phenyl-2-hydroxypropionyl)-L-alaninyl] amino-2 ,3dihydro-l1-methyl-5-(2-pyridyl)- 1H- 1,4-benzodiazepin-2-one WO 98t28268 PTU9128 PCTIUS97/22986 381 8-68 3-[N '-(phenyl-ca-hydroxyacetyl)-L-alaninyl]amino-2 ,3dihydro- 1-methyl-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 8-69 3-[N '-(4-chlorophenyl-at-hydroxyacetyl)-L-alaninyl] amino- 2 ,3-dihydro- 1-methyl-5-(2-pyridyl)-l1-i,4-benzodiazepin-2one 8-70 .3-[N'-(3-methylbutyryl)-L-aianinyllamino-2 ,3-dihydro- 1methyl-5-(2-pyridyl)- 1H- 1,4-benzodiazepin-2-one 8-71 3-[N ,5-trifluorophenylacetyl)-L-alaninyl] amino-2 ,3dihydro- 1-methyl-5-(2-pyridyl)- 1H- 1,4-benzodiazepin-2-one 8-72 -(3-methylthiopropionyl)-L-alaninyljamino-2 ,3-dihydro- 1 -methyl-5-(2-pyridyl)-1W- 1 ,4-benzodiazepin-2-one 8-73 3-[N'-(3-methyl-2-hydroxybutyryl)-L-alaninyljamino-2, 3dihydro-l1-methyl-5-(2-pyridyl)-l1i,4-benzodiazepin-2-one 8-74 3-[N '-(3-nitrophenylacetyl)-L-alaninyl]amino-2, 3-dihydro- 1 methyl-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 8-75 3-[N '-(4-methoxyphenylacetyl)-L-alaninyl]amino-2 ,3-dihydro- 1 -(tert-butylcarbonylmethyl)-5-(2-pyridyl)- 1H- 1,4benzodiazepin-2-one 8-76 3-[N'-(2-thienylacetyl)-L-alaninyl]amino-2, 3-dihydro-lI-(tertbutylcarbonylmethyl)-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2one 8-77 3-[N ,5-difluorophenylacetyl)-L-alaninyl]aniino-2, 3diliydro- 1-(tert-butyicarbonylmethyl)-5-(2-pyridy1)-i H- 1,4benzodiazepin-2-one 8-78 3-[N '-(3-bromophenylacetyl)-L-alaninyl] amino-2 ,3-dihydro- 1- (tert-butylcarbonylmethyl)-5-(2-pyridyl)- 1 H-i ,4benzodiazepin-2-one 8-79- -(2-phenylthioacetyl)-L-alaninyllaniino-2 ,3-dihydro- 1- (tert-butylcarbonylmethyl)-5-(2-pyridyl)-l1i,4benzodiazepin-2-one 8-80 3-IN' -(4-ethoxyphenylacetyl)-L-alaninyllamino-2 ,3-dihydro- 1 -(tert-butylcarbonylmethyl)-5-(2-pyridyl)-l1i,4benzodiazepin-2-one WO 98/28268 PCTfUS97/22986 382 8-81 3-[N '-(4-trifluoromethylphenylacetyl)-L-alaninyl]aniino-2 ,3dihydro-l1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)- 1H- 1,4benzodiazepin-2-one 8-82 alaninyl]amino-2 ,3-dihydro-l1-(tert-butylcarbonylmethyl)-5-(2pyridy 1)-iH-i ,4-benzodiazepin-2-one 8-83 -(2-methylthioacetyl)-L-alaninyllamino-2 ,3-dihydro- 1 (tert-butylcarbonylmethyl)-5-(2-pyridyl)-l11-1,4benzodiazepin-2-one 8-84 3-[N '-(2-cyclomethylacetyl)-L-alaninyl]amino-2 ,3-dihydro- 1- (terrt-butylcarbonylmethyl)-5-(2-pyridyl)- 1H- 1,4benzodiazepin-2-one 8-85 3-[N ,6-pentafluorophenyloxyacetyl)-Lalaninyllamino-2 ,3-dihydro-l1-(:ert-butylcarbonylmethyl)-5-(2pyridyl)-1H- 1,4-benzodiazepin-2-one 8-86 3- -(thionaphth-3-ylacetyl)-L-alaninyllamino-2 ,3-dihydro- 1 (tert-butylcarbonylmethyl)-5-(2-pyridyl)- 1H- 1,4benzodiazepin-2-one 8-87 ,6-trimethylphenylacetyl)-L-alaninyl~amino-2,3dihydro-l1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-l1H- 1,4benzodiazepin-2-ohe 8-88. -((4-phenyl)phenylacetyl)-L-alaninyllamino-2 ,3-dihydro- 1 -(tert-butylcarbonylmethyl)-5-(2-pyridyl)- 1H-1,4benzodiazepin-2-one 8-89 3-[N ,4-difluorophenylacetyl)-L-alaninyljamino-2 dihydro-l1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-l1H- 1,4benzodiazepin-2-one 8-90* 3-[N '-(4-(2-thienyl)butyryl)-L-alaninyljamino-2 ,3-dihydro- 1- (tert-butylcarbonylmethyl)-5-(2-pyridyl)-l1H- 1,4benzodiazepin-2-one 8-91 3-[N '-(5-methylhexanoyl)-L-alaninyl]amino-2 ,3-dihydro- 1- (tert-butylcarbonylmethyl)-5-(2-pyridyl)- 1H- 1,4benzodiazepin-2-one WO 98/28268 PCT1US97/22986 383 8-95 3-[N ,6-difluorophenyl-ca-hydroxyacetyl)-Lalaninyljamino-2,3-dihydro- 1-(tert-butylcarbonylmethyl)-5-(2pyridyl)- 1 H-i ,4-benzodiazepin-2-one 8-96 3- -(4-fluorophenyl-ae-hydroxyacetyl)-L-alaninyl] amino- 2, 3-dihydro- 1 -(tert-butylcarbonylmethyl)-5-(2-pyridyl)- 1H- 1 ,4-benzodiazepin-2-one 8-97 3- alaninyl]amino-2, 3-dihydro- 1 -(tert-butylcarbonylmethyl)-5-(2pyridyl)- 1H-1 ,4-benzodiazepin-2-one 8-98 ,6-trifluorophenylacetyl)-L-alaninyl] amino-2 ,3dihydro-l1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-l1H- 1,4benzodiazepin-2-one 8-99 3- -(2-trifluoromethyl-4-fluorophenylacetyl)-Lalaninyl]aniino-2,3-dihydro-l1-(tert-butylcarbonylmethyl)-5-(2pyridyl)- lH- 1,4-benzodiazepin-2-one 8-100 3- [N '-(4,4,4-trifluorobutyryl)-L-alaninyl]amino-2 ,3-dihydro- 1 -(tert-butylcarbonylmethyl)-5-(2-pyridyl)-l1H- 1,4benzodiazepin-2-one 8-101 3-[N'-(4-iso-propyphenyacety)-L-alaninyl amino-2 ,3dihydro- 1 -(tert-butylcarbonylmethyl)-5-(2-pyridyl)- 1 H- 1,4benzodiazepin-2-one 8-102 3-[N '-(3-phenyl-2-hydroxypropionyl)-L-alaninyl]amino-2 .3dihydro-l1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)- 1H- 1,4benzodiazepin-2-one 8-103 3- -(phenyl-oa-hydroxyacetyl)-L-alaninyl]amino-2 .3dihydro- 1 -(tert-butylcarbonylmethyl)-5-(2-pyridyl)- 1 H- 1,4benzodiazepin-2-one 8-104 -(4-chlorophenylacetyl)-L-alaninyl]amino-2 ,3-dihydro- 1- (tert-butylcarbonylmethyl)-5-(2-pyridyl)- 1H- 1,4benzodiazepin-2-one 8-105 3- -(3-methylbutyryl)-L-alaninyl]amino-2 ,3-dihydro- 1 -(tenbutylcarbonylmethyl)-5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2- Sone WO 9=/8268 PCTIUS97/22986 384 8-106 8-107 8-108 8-109 8-110 8-111 8-112 3-[N 5-trifluorophenylacetyl)-L-alarnnyl] amino-2 ,3dihydro- 1 -(tert-butylcarbonyhnethyl)-5-(2-pyridyl)- 1 H- 1,4benzodiazepin-2-one 3-[N '-(3-met11ylthiopropiony1)-L-alaninyllamino-2 ,3-dihydro- 1 -(tert-butyIcarbonylmethy1)-5-(2-pyridy)- IH- 1,4benzodiazepin-2-one 3-[N '-(3-methyl-2-hydroxybutyryl)-L-alaninyl] amino-2 ,3dihydro-l1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-l1H- 1,4benzodiazepin-2-one 3-[N '-(3-nitrophenylacetyl)-L-alaninyl]amino-2 ,3-dihydro- 1- (tert-butylcarbonylmethyl)-5-(2-pyridyl)- 1H- 1,4benzodiazepin-2-one 3-[N methoxyphenylacetyl)-L-alaninyl]amino-2 ,3-*dihydro- 1 ,N-diethylamino)ethyl)-5-(2-pyridyl)- 1H- 1,4benzodiazepin-2-one 3-[N '-(2-thienylacetyl)-L-alaninyllamino-2 ,3-dihydro-l1-(2- (N,N-diethylaniino)ethyl)-5-(2-pyridyl)- 1H- 1,4benzodiazepin-2-one ,5-difluorophenylacetyl)-L-alaninyl]amino-2, 3dihydro-l1-(2-(N, N-diethylamino)ethyl)-5-(2-pyridyl)- 1H- 1,4benzodiazepin-2-one 3- -(3-bromophenylacetyl)-L-alaninyllamino-2 ,3-dihydro- 1- ,N-diethylamino)ethyl)-5-(2-pyridyl)- 1H- 1,4benzodiazepin-2-one 3- -(2-phenylthioacetyl)-L-alaninyllamino-2 ,3-dihydro- 1- ,N-diethylamino)ethyl)-5-(2-pyridyl)- 1H- 1,4benzodiazepin-2-one 3-[N '-(2-cyclohexylacetyl)-L-alaninyljamino-2 ,3-dihydro- 1- (2-(N,N-diethylaniino)ethyl)-5-(2-pyridyl)- 1H-1 ,4benzodiazepin-2-one 3-[N ,6-pentafluorophenyloxyacetyl)-Lalaninyl]amino-2, 3-dihydro-l1-(2-(N, N-diethylamino)ethyl)-5 (2-pyridy 1)-iH-i ,4-benzodiazepin-2-one 3-[N '-(2-thionaphth-3-ylacetyl)-L-alaninyllamino-2 ,3-dihydro- 1 ,N-diethylamino)ethyl)-5-(2-pyridyl)-l1H- 1,4berizodiazepin-2-one 8-113 8-114 8-117 8-118 8-119 WO 98/28268 PCTIVS97/22986 385 8-120 3-[N '-(2-phenyl-2-oxoacetyl)-L-alaninyl]amino-2 ,3-dihydro- 1 N-diethylamino)ethyl)-5-(2-pyridyl)-l1H- 1,4benzodiazepin-2-one 8-123 3-[N ,4-difluorophenyl)acetyl)-L-alaninyl] amino-2 ,3dihydro- 1 N-diethylamino)ethyl)-5-(2-pyridyl)- 1 H- 1,4benzodiazepin-2-one 8-124 -((4-(thien-2-yl)butyryl)-L-alaninyl] amino-2 ,3-dihydro- 1 ,N-diethylamino)ethyl)-5-(2-pyridyl)- 1H- 1,4benzodiazepin-2-one 8-125 3-[N '-(5-methylhexanoyl)-L-alaninyllamino-2 ,3-dihydro-l1-(2- N-diethylaniino)ethyl)-5-(2-pyridyl)- 1H- 1,4benzodiazepin-2-one 8-130 3 '-(4-fluorophenyl-ca-hydroxyacetyl)-L-alaninyl] amino- 2, 3-dihydro-l1-(2-(N, N-diethylamino)ethyl)-5-(2-pyridyl)-l1H- 1 ,4-benzodiazepin-2-one 8-131 3-[N alaninyl]amino-2,3-dihydro- 1-(2-(N,N-diethylamino)ethyl)-5- (2-pyridyl)-LH-1 ,4-benzodiazepin-2-one 8-135 3-[N ,4-trifluorobutyryl)-L-alaninyl]amino-2 ,3-dihydro- 1 N-diethylamino)ethyl)-5-(2-pyridyl)-l1H- 1,4benzodiazepin-2-one 8-136 3-[N '-(4-iso-propylphenylacetyl)-L-alaninyl] amino-2 ,3dihydro- I ,N-diethylamino)ethyl)-5-(2-pyridyl)- 1 H- 1,4benzodiazepin-2-one 8-137 3-[N '-(3-phenyl-2-hydroxypropionyl)-L-alaninyl] amino-2 ,3dihydro- 1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)- 1H- 1,4benzodiazepin-2-one 8-138 -(phenyl-ce-hydroxyacetyl)-L-alaninyl] amino-2 .3dihydro- ,N-diethylamino)ethyl)-5-(2-pyridyl)- 1 H- 1,4benzodiazepin-2-one 8-139 3-[N '-(4-chlorophenyl-a-hydroxyacetyl)-L-alaninyl] amino- 2, 3-dihydro- 1 ,N-diethylamino)ethyl)-5-(2-pyridyl)- 1H- 1 ,4-benzodiazepin-2-one WO 98/28268 PCT1US97/22986 386 Example 8-140 Synthesis of 3-[N'-(3,5-Difluorophenyl-ae-hydroxyacetyl)- L-3-thienylglycinyllamino-2,4- 'dioxo- 1,5-bis(2,2-dimethylpropyl)-2,3,4,5-tetrahydro.
Ili- Following General Procedure D above using 3,5-difluoromandelic acid (Fluorochem) and 3-(L-3-thienylglycinyl] amino-2 ,4-dioxo- 1,5-bis(2 ,2dimethylpropyl)-2 ,3,4 ,5-tetrahydro-l1H-i, 5-benzodiazepine (Example 8-AB), the title compound was prepared as a solid. The product was purified by LC 2000 chromatography, eluting with hexanes/ethyl acetate Isomer 1: Melting Point: 191-192'C.
Optical Rotation: +21.47 589; +52.17 365 (c 1, MeOH).
C
33
H
38
F
2
N
4 0 5 S (MW 640); mass spectroscopy found (M 639.1; 640.1.
Anal. calcd for C 33
H
38
F
2
N
4 0 5 S: C, 61.68; H, 5.89; N, 8.74. Found: C, 61.87; H, 6.08; N, 8.84.
Isomer 2: Melting Point: 230-231' 0
C.
Optical Rotation: +59.26 589; +200.0 365 (c 1, MeOH).
C
33
H
38
F
2
N
4 0 5 S (MW 640); mass spectroscopy found 639.4; 640.4.
Anal. calcd for C 33
H
38
F
2
N
4 0 5 S: C, 61.68; H, 5.89; N, 8.74. Found: C, 62.01; H, 6.07; N, 8.52.
Example 8-141 Synthesis of 3 2 4 -dioxo-1-phenyl-5-methyl-2,3,4,5-tetrahydro-1H- Following General Procedure D above using 3,5-difluoromandelic acid (Fluorochem) and 3-(L-alaninyl)amino-2 ,4-dioxo-l1-phenyl-5-methyl-2,3,4,5tetrahydro-1H-1 ,5-benzodiazepine (Example the title compound was WO 98/28268 PCT1US97/22986 387 prepared as a solid. The product was purified by LC 2000 chromatography, eluting with hexanes/ethyl acetate (30:70).
Isomer 1: Melting Point: 212-213*C.
Optical Rotation: [a]l +101.34 589; +491.4 365 (c 1, MeOH).
C
2 7H 24
F
2
N
4 0 5 (MW 522.17); mass spectroscopy found 523.3; 521.3.
Isomer 2: Melting Point: 282-283 0
C.
C
27
H
24
F
2
N
4 0 5 (MW 522.1793); exact mass spectroscopy found 523.1800.
Isomer 3: Melting Point: 147-148*C.
C
27
H
24
F
2
N
4 0 5 (MW 522.1793); exact mass spectroscopy found 523.1793.
Isomer 4: Melting Point: 255-256*C.
C
27
H
24
F
2
N
4 0 5 (MW 522.17); mass spectroscopy found 523.2.
Anal. calcd for C 27
H
24
F
2
N
4 0 5 C, 62.07; H, 4.63; N, 10. 72. Found: C, 62.18; H, 4.84; N, 10.74.
Example 8-142 Synthesis of' 3-IN'-(3,5-Difluorophenyl-a-hydroxyacetyl)-L-alaninyllamino- 2-oxo-1-metbyl-5-phenyl-1 ,3,4,5-tetrahydro-1H-1 Following General Procedure D above using 3,5-difluoromandelic acid (Fluorochem) and 3-(L-alaninyl)amino-2-oxo-l1-methyl-5-phenyl- 1,3,4,5tetrahydro-1H-1,5-benzodiazepine (Example the title compound was prepared as a solid. The product was purified by LC 2000 chromatography, eluting with hexanes/ethyl acetate (40:60).
Isomer 1: Melting Point: 2587259*C.
WO 98/28268 PTU9/28 388
C
2 7
H-
2
AFN
4 0 4 (MW 508); mass spectroscopy found 507; 508.
Anal. calcd for C 27
H
26
F
2
N
4 0 4 C, 63.77; H, 5.16; N, 11 .02. Found: C, 63.84; H, 5.34; N, 10.96.
Isomer 2:
C
27
H
26
F
2
N
4 0 4 (MW 508); mass spectroscopy found 507; 508.
Anal. calcd for C 27
H
26
F
2
N
4 0 4 C, 63.77; H, 5.16; N, 11.02. Found: C, 63.74; H, 5.38; N, 10.76.
Isomer 3: Melting Point: 121-123*C.
C
27
H-
26 F7 2
N
4 0 4 (MW 508); mass spectroscopy found 507; 508.
Anal. calcd for C 27
H
26
F
2
N
4 0 4 C, 63.77; H, 5.16; N, 11.02. Found: C, 63.55; H, 5.30; N, 10.74.
Isomer 4: Melting Point: 204-205 0
C.
C
27 H1 2
AFN
4 0 4 (MW 508); mass spectroscopy found 507; 508.
Anal. calcd for C 27 H1 26 FAN0 4 C, 63.77; H, 5.16; N, 11.02. Found: C, 63.23; H, 5.24; N, 10.74.
Example 8-143 Synthesis of 3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]amino- L-LH-imidazole[1,2-a]-6-phenyl-1 ,4-benzodiazepine Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)amino-L-l1H-imidiazole[ 1,2-a] -6phenyl-1 ,4-benzodiazepine (prepared by the methods described in Bock et al., Bioorganic and Medicinal Chemistry, Vol. 2, 987-988 (1994); J. Med. Chem., 1988, 31, 176-181; and J. Org. Chem., 1987, 52, 3232), the title compound was prepared as a solid. The product was purified by LC 2000 chromatography, eluting with methanol/dichloromethane (5:95).
Isomer 1: Melting Point: 205-206'C.
Optical Rotation: -12.86 589; -135.05 365 (c 1, MeOH).
WO 98/28268 PTU9128 PCT/US97/22986 389
C
28
H,
3
F
2
N
5 0 2 (MW 499); mass spectroscopy found (M H) 499. 1.
Anal. calcd for C 28
H
23
F
2
N
5 0 2 C, 67.33; H, 4.64; N, 14.02. Found: C, 67.49; H, 4.61; N, 13.77.
Isomer 2: Melting Point: 151-153*C.
Optical Rotation: -37.41 589; -114.71 365 (c 1, MeOH).
C
28 H1.
3
F
2
N
5
O
2 (MW 499.1894); exact mass spectroscopy found (M H) 499.1898.
Anal. calcd for C 2
,H
23
F
2
N
5 0 2 C, 67.33; H, 4.64; N, 14.02. Found: C, 63.43; H, 4.36; N, 13.10.
Example 8-144 Synthesis of 4-[N'-(3,5-Difluorophenylacetyl)-L-alaninyljamino- L- 1H-imidazole[1 ,2-a]-2,4-dihydro-6-phenyl-1 ,4-benzodiazepine Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)amino-L- 1H-imidazole[ 1,2-a] -2,4dihydro-6-phenyl- 1,4-benzodiazepine (prepared by the methods described in Bock et al., Bicorganic and Medicinal Chemistry, Vol. 2, 987-988 (1994); J.
Med. Chem., 1988, 31, 176-181; and J. Org. Chem., 1987, 52, 3232), the title compound was prepared as a solid. The product was purified by LC 2000 chromatography, eluting with methanol/dichloromethane (5:95).
Isomer 1: Melting Point: 135-136'C.
Optical Rotation: 15.63 589; -162.5 365 (c 1, MeOH).
C
28 H25F 2
N
5
O
2 (MW 501.2); mass spectroscopy found (M 501.1.
Anal. calcd for C 28 H25F 2
N
5
O
2 C, 67.06; H, 5.02; N, 13.96. Found: C, 62.9; H, 4.93; N, 12.53.
Isomer 2: Melting Point: 162-165 0
C.
Optical Rotation: -28.66 589; -76.43 365 (c 1, MeGH).
WO 98/28268 PCT/US97/22986 390
C
2
JH
25
F
2
N
5 0 2 (MW 502.2050); exact mass spectroscopy found (M+H) 502.2050.
Anal. calcd for C 2 8 H25 2
N
5 0 2 C, 67.06; H, 5.02; N, 13.96. Found: C, 62.70; H, 4.78; N, 12.69.
Example 8-145 Synthesis of 4{[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]amino- L-4H Iii,2,4]triazole[4,3-a]-6-phenyl-1 ,4-benzodiazepine Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)amino-L-4H[ 1,2 ,4]triazole[4 6-phenyl-1 ,4-benzodiazepine (prepared by the methods described in Bock et al., Bioorganic and Medicinal Chemistry, Vol. 2, 987-988 (1994); J. Med. Chem., 1988, 31, 176-181; and J. Org. Chem., 1987, 52, 3232), the title compound was prepared as a solid 165-167*C). The product was purified by LC 2000 chromatography, eluting with methanol/dichoromethane Optical Rotation: [ax] -34.63 589; -138.53 365 (c 1, MeGH).
C2 7
H
22
F
2
N
6 0 2 (MW 500); mass spectroscopy found 500.1.
Anal. calcd for C 27
H
22
F
2
N
6 0 2 C, 64.79; H, 4.43; N, 16.79. Found: C, 63.01; H, 4.73; N, 15.32.
Example 8-146 Synthesis of 3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyllamino-2,4-dioxo- 1 ,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine Following General Procedure I above using alanine (Example B) and 3-amino-2 ,4-dioxo- 1,5-bis-( 1-methylethyl)-2,3,4,5tetrahydro- 1H-i ,5-benzodiazepine (Example the title compound was prepared as a white solid (melting point 232-233*C). Purification was by flash chromatography eluting with EtOAc/hexanes 1 gradient to 6: Rf 0.31 (4:1 EtOAc/hexanes).
C
26
H
30
F
2
N
4 0 4 (MW 500.55); mass spectroscopy 500.2 WO 98/28268 PCTI'US97/22986 391 Anal. Calcd. for C 26
H
30
F
2
N
4 0 4 C, 62.39; H, 6.04; N, 11. 19. Found: C, 62.62; H, 6.00; N, 11.21.
Example 8-147 Synthesis of 3-[N'-(3,5-Difluorophenylacetyl)-(R)-2-thienylglycinyllamino- 2,4-dioxo-1,5-bis-(1-methylethyl)- 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine Following General Procedure I above using 3,5-difluorophenylacetic acid (Lancaster) and 3-(R-2-thienylglycinyl)-amino-2 ,4-dioxo- 1, 5-bis-( 1-methylethyl)- 2,3,4, 5-tetrahydro- 1H-i, 5-benzodiazepine hydrochloride (Example the title compound was prepared as an amorphous white solid. Purification was by flash chromatography eluting with CH 2 Cl 2 /EtOAc (5:1 gradient to 4: Rf 0.34 (4:1 CH 2 Cl 2 /EtOAc).
C
29
H
30
F
2
N
4 0 4 S (MW 568.65); mass spectroscopy 568.
Anal. Calcd. for C 2 qH 30
F
2
N
4 0 4 S: C, 61.25; H, 5.32; N, 9.85. Found: C, 61.00; H, 5.42; N, 9.68.
Example 8-148 Synthesis of 3-[N'-(Cyclopropylacetyl)-R-2-thienylglycinyljamino- 2,4-dioxo-1 ,5-bis-(1-methylethyl)-2,3,4,5tetrahydro-1H-1 Following General Procedure I above using cyclopropylacetic acid (Lancaster) and the product from Example 8-Q, the title compound was prepared as an amorphous white solid. Purification was by flash chromatography eluting with CH 2 Cl,/EtOAc (4:1 gradient to Rf 0.26 1 CH 2 Cl,/EtOAc).
C
26
H
32
N
4 0 4 S (MW 496.63); mass spectroscopy (MH 496.5 Anal. Calcd. for C 26
H
32
N
4 0 4 S: C, 62.88; H, 6.49; N, 11.28. Found: C, 62.65; H, 6.57; N, 11.55.
WO 98/28268 PCTrIUS97/22986 392 Example 8-149 Synthesis of 3 -[N'-(Cyclopentylacetyl)-R-2-thienylglycinyllaminotetrahydro-1H-1 Following General Procedure I above using cyclopentylacetic acid (Aldrich) and the product from Example 8-Q, the title compound was prepared as an amorphous white solid. Purification was by flash chromatography eluting with
CH
2 Cl 2 /EtOAc (5:1 gradient to Rf 0.26 (4:1 CH 2
CI
2 /EtOAc).
C
28
H
36
N
4 0 4 S (MW 524.69); mass spectroscopy (MH 524.5 Anal. Calcd. for C 28
H
36
N
4 0 4 S: C, 64.10; H, 6.92; N, 10.68. Found: C, 64.07; H, 6.91; N, 10.67.
Example 8-150 Synthesis of 3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]amino- 2,4-dioxo-1 ,5-bis-methyl-2,3,4,5-tetrahydro- 1H-1 Following General Procedure I above using 3,5-difluorophenylacetic acid (Lancaster) and 3-(L-alaninyl)-amino-2 ,4-dioxo- 1,5-bis-methyl-2 ,3,4,5tetrahydro-LH- 1, 5-benzodiazepine hydrochloride (Example the title compound was prepared as a white solid (melting point 206-207 0
C).
Purification was by flash chromatography eluting with straight EtOAc gradient to EtOAc/Acetone Rf 0.32 (EtOAc).
C
22
H
22
F
2
N
4 0 4 (MW 444.42); mass spectroscopy 444.
Anal. Calcd. for C 22
H
22
F
2
N
4 0 4 C, 59.46; H, 4.99; N, 12.61. Found: C, 59.54; H, 5.09; N, 12.56.
Example 8-151 Synthesis of 3 3 ,S-Difluorophenyl-oe-hydroxyacetyl)-L-alaninyljamino- 2,4-dioxo-1 ,5-bis-methyl-2,3,4,5-tetrahydro-1H-1 Following General Procedure I above using 3,5-difluoromandelic acid (Lancaster) and the product from Example 8-R, the title compound was WO 98/28268 PCT/U597/22986 393 prepared as an amorphous white solid. Purification was by L.C. 2000 eluting with straight EtOAc then flash chromatography eluting with CH 2
CI
2 /Acetone 1 gradient to 3: Rf 0. 39 and 0. 34 (EtOAc).
C
22
H
22
F
2
N
4 0 5 (MW 460.44); mass spectroscopy (MH 461.0.
Anal. Calcd. for C 22
H
22
F
2
N
4 0 5 C, 57.39; H, 4.82; N, 12.17. Found: C, 57.16; H, 4.88; N, 11.97.
Example 8-152 Synthesis of 3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]amino- 2,4-dioxo-1 ,5-bis-(2-methylpropyl)-2,3,4,5tetrahydro-1H-1 Following General Procedure I above using 3 ,5-difluorophenylacetic acid (Lancaster) and 3-(L-alaninyl)amino-2 ,4-dioxo- 1,5-bis-(2-methylpropyl)-2 ,3 tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example the title compound was prepared as a white solid (melting point 197-198*C).
Purification was by flash chromatography eluting with CH 2 Cl 2 /EtOAc (2:1 gradient to Rf 0.23 (CH 2 Cl 2 /EtOAc, 1: 1).
C
28
H
34
F
2
N
4 0 4 (MW 528.60); mass spectroscopy (MH 528.
Anal. Calcd. for C 28
H
34
F
2
N
4 0 4 C, 63.62; H, 6.48; N, 10.60. Found: C, 63.75; H, 6.63; N, 10.67.
Example 8-153 Synthesis of 3-[N'-(Cyclopentylacetyl)-L-alaninyl]amino-2,4-dioxo- 1 ,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1 Following General Procedure I above using cyclopentylacetic acid (Aldrich) and 3-(L-alaninyl)amino-2 ,4-dioxo- 1, 5-bis-(2-methylpropyl)-2 ,3,4 1H-1 ,5-benzodiazepine hydrochloride (Example the title compound was prepared as an amorphous white solid. Purification was by flash chromatography eluting with CH 2 Cl 2 /EtOAc Rf 0.31 (CHCl 2 /EtOAc, 1: 1).
C,
7 H4ON 4
O
4 (MW 484.64); mass spectroscopy (MH 484.
WO 98=8268 PCT1US97/22986 394 Anal. Calcd. for C 27
H
40
N
4 0 4 C, 66.92; H, 8.32; N, 11.56. Found: C, 66.86; H, 8.64; N, 11.41.
Example 8-154 Synthesis of 3-[N'-(Cyclopropylacetyl)-L-alaninyl]-amino-2,4-dioxo- 1 ,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1 Following General Procedure I above using cyclopropylacetic acid (Lancaster) and 3-(L-alaninyl)amino-2 ,4-dioxo- 1, 5-bis-(2-methylpropyl)-2,3,4,5tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example the title compound was prepared as a white solid (melting point 190-191 Purification was by flash chromatography eluting with CH 2 Cl 2 /EtOAc 1 gradient to 3:4) and a second flash chromatography eluting with EtOAc/Toluene Rf 0.28 (EtOAc/Toluene, 7:3).
C
25
H
36
N
4 0 4 (MW 456.59); mass spectroscopy (MH 456. 1.
Anal. Calcd. for C 25
H
36
N
4 0 4 C, 65.77; H, 7.95; N, 12.27. Found: C, 66.01; H, 8.03; N, 12.35.
Example 8-155 Synthesis of 3-[N'-(3,5-Difluorophenylacetyl)-Sphenylglycinylj-amino-2,4-dioxo-1 ,5-bis-(2-methylpropyl)- 2,3,4,5-tetrahydro-1H-1 Following General Procedure I above using 3,5-difluorophenylacetic acid (Lancaster) and 3-(S-phenylglycinyl)-amino-2 ,4-dioxo- 1,5-bis-(2-methylpropyl)- 2,3,4 ,5-tetrahydro- 1H-i, 5-benzodiazepine hydrochloride (Example the title compound was prepared as a white solid (melting point 186-187'C).
Purification was by flash chromatography eluting with CH 2 Cl 2 /EtOAc (7:1 gradient to 4: Rf 0. 39 (CHCl,/EtOAc, 7: 1).
C
33
H
36
F
2
N
4 0 4 (MW 590.68); mass spectroscopy 590.0.
Anal. Calcd. for C 33
H
36
F
2
N
4 0 4 C, 67. 10; H, 6.14; N, 9.49. Found: C, 67.36; H, 6.38; N, 9,56.
WO 98/28268 PCT/US97/22986 395 Example 8-156 Synthesis of 3-IIN'-(3,5-Difluorophenylacetyl)-L-alaninyl]-amiino- 2,4-dioxo-1 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine Following General Procedure I above using 3,5-difluorophenylacetic acid (Lancaster) and 3-(L-alaninyl)-amino-2 ,4-dioxo- 1, 2,3,4, 5-tetrahydro- 1H-i ,5-benzodiazepine hydrochloride (Example the title compound was prepared as a white solid (melting point 21 1-212 0
C).
Purification was by flash chromatography eluting with CH 2 Cl 2 /EtOAc 1 gradient to Rf 0.44 (CH 2 Cl 2 IEtOAc, 1: 1).
C
28
H
30
F
2
N
4 0 4 (MW 524.57); mass spectroscopy (MH 524. 1.
Anal. Calcd. for C 28
H
30
F
2
N
4 0 4 64.11; H, 5.76; N, 10.68. Found: C, 64.07; H, 5.79; N, 10.49.
Example 8-157 Synthesis of 3-[N'-(Cyclopentylacetyl)-L-alaninyl]-amiino- 2 ,4-dioxo-1 2,3,4,5-tetrahydro- 1H-1,5-benzodiazepine Following General Procedure I above using cyclopentylacetic acid (Aldrich) and 3-(L-alaninyl)-amino-2 ,4-dioxo- 1,5-bis-(cyclopropylmethyl)-2 ,3,4,5tetrahydro- 1H- 1,5-benzodiazepine. hydrochloride (Example the title compound was prepared as a white foam. Purification was by flash chromatography eluting with CH 2 Cl 2 /EtOAc 1 gradient to Rf 0.
(CH
2 Cl 2 /EtOAc, 1: 1).
C
27
H
36
N
4 0 4 (MW 480.61); mass spectroscopy 481.2 and (MH-) 479.2.
Anal. Calcd. for C 27 H1 36
N
4 0 4 C, 67.48; H, 7.55; N, 11.66. Found: C, 67.33; H, 7.57; N, 11.37.
WO 98/28268 WO 9828268PCTIUS97/22986 396 Example 8-158 Synthesis of 3-[N'-(Cyclopenty1-ca-hydroxyacetyl)-L-alaninyl]-amnino- 2,4-dioxo-1 ,5-bis-(cyclopropylmethyi)-2,3,4,5tetrahydro-1H-1 Following General Procedure I above using cyclopentyl-cr-hydroxyacetic acid (Example P) and 3-(L-alaninyl)-amino-2,4-dioxo-l,5-bis- (cyclopropylmethyl)-2 5-tetrahydro-l1H-i ,5-benzodiazepine hydrochloride (Example the title compound was prepared as a white foam. Purification was by L.C. 2000 eluting with CH 2 Cl 2 /EtOAc (1:1 gradient to 1:2) then flash chromatography eluting with 2:1 EtOAc/CH 2
C
2 R, 0.47 and 0.37
(CH
2
CI
2 /EtOAc, 1:2).
C
27
H
36
N
4 0 5 (MW 496.61); mass spectroscopy 497.2 and (MH-) 495.2 Anal. Calcd. for C 27
H
36
N
4 0 5 C, 65.30; H, 7.31; N, 11.28. Found: C, 65.01; H, 7.35; N, 11.28.
Example 8-159 Synthesis of 3-[N'-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino- 2,4-dioxo-1 ,5-bis-(2,2-dimethylpropyl)-2,3,4,5tetrahydro-1H-1 Following General Procedure I above using 3,5-difluorophenylacetic acid (Lancaster) and 3-(L-alaninyl)-amino-2 ,4-dioxo- 1, 5-bis-(2, 2-dimethyipropyl)- 2,3 ,4,5-tetrahydro- 1H- 1,5-benzodiazepine hydrochloride (Example the title compound was prepared as a white solid (melting point 194-195 0
C).
Purification was by flash chromatography eluting with CHC1 2 /EtOAc (2:1 gradient to Rf 0.46 (CH 2
CI
2 /EtOAc, 2: 1).
C
30
H
38
F
2
N
4 0 4 (MW 556.66); mass spectroscopy 557.0 (MH-) 555.4.
Anal. Calcd. for C 30
H
38
F
2
N
4 0 4 C, 64.73; H, 6.88; N, 10.06. Found: C, 64.45; H, 6.82; N, 10.08.
WO 98/28268 PTU9128 PCTIUS97/22986 397 Example 8-160 Synthesis of 3-[N'-(3,5-Difluoropheny-a-hydroxyacety)LalaninyI}..ino.
2,4-dioxo-1 ,5-bis-(2,2-dimethylpropyl)-2,3, tetrahydro-lH-1 Following General Procedure I above using 3,5-difluoromandelic acid (Lancaster) and 3-(L-alaninyl)-aniino-2 ,4-dioxo- 1,5-bis-(2 ,2-dimethylpropyl)- 2,3,4,5-tetrahydro-1H-1 ,5-benzodiazepine hydrochloride (Example the title compound was prepared as a white solid (melting point 1 16-126*C).
Purification was by flash chromatography eluting with CH 2
CI
2 /EtOAc 1 gradient to Rf 0.54 and 0.40 (CH 2
CI
2 /EtOAc, 1: 1).
C
30
H
3 gF 2
N
4 0 5 (MW 572.66); mass spectroscopy (MH 573.4 (MH-) 571.6.
Anal. Calcd. for C 30
H
38
F
2
N
4 0 5 62.92; H, 6.69; N, 9.78. Found: C, 62.86; H, 6.54; N, 9.65.
Example 8-161 Synthesis of 3-[N'-(Cyclopentylacetyl)-L-alaninyllamino-2 ,4-dioxo- 1,5-bis-(2,2-dimethylpropyl)-2,3,4,5tetrahydro-1H-1 Following General Procedure I above using cyclopentylacetic acid (Aldrich) and 3-(L-alaninyl)-amino-2 ,4-dioxo- 1, 5-bis-(2 ,2-dimethylpropyl)-2 ,3,4,5tetrahydro-1H-1 ,5-benzodiazepine hydrochloride (Example the title compound was prepared as a white amorphous solid. Purification was by flash chromatography eluting with CH 2
CI
2 /EtOAc (2:1 gradient to Rf 0.29
(CH
2 Cl 2 /EtOAc, 2: 1).
C
29 H44N 4
O
4 (MW 512.70); mass spectroscopy (MH 513.6 511.6.
Anal. Calcd. for C 29 H44N 4
O
4 C, 67.94; H, 8.65; N, 10.93. Found: C, 68.18; H, 8.60; N, 10.68.
WO 98/28268 PCT1US97/22986 398 Example 8-162 Synthesis of 3-[N'-(Cyclopenityl-a-hydroxyacetyl)-L-alaninyljamino-2,4.dioxo- 1,5-bis-(2,2-dimethylpropyl)-2,3,4,5tetrahydro-1H-1 Following General Procedure I above using cyclopentyl-Cf-hydroxyacetic acid (Example P) and 3-(L-alaninyl)-amino-2 ,4-dioxo- 1,5-bis-(2 ,2dimethylpropyl)-2 ,3,4 ,5-tetrahydro-l1H-i ,5-benzodiazepine hydrochloride (Example the title compound was prepared as a white solid (melting point =1 19-129*C). Purification was by flash chromatography eluting with
CH
2 Cl 2 /EtOAc (1:1 gradient to Rf 0.42 and 0.28 (CH 2 Cl.,/EtOAc, 1: 1).
C
29 H44N 4
O
5 (MW 528.70); mass spectroscopy 529.2 527.4.
Anal. Calcd. for C 29 H14N 4
O
5 C, 65.88; H, 8.39; N, 10.60. Found: C, 65.56; H, 8.03; N, 10.35.
Example 8-163 Synthesis of 3-[N'-(3,5-Difluorophe'nylacetyl)-L-alaninyl-amino-2 ,4-dioxo- 1 ,5-bis-phenyl-2,3,4, 5-tetrahydro-1H-1 Following General Procedure I above using 3,5-difluorophenylacetic acid (Lancaster) and 3-(L-alaninyl)-amino-2 ,4-dioxo- 1, 5-bis-phenyl-2,3,4,5tetrahydro-1H-1,5-berizodiazepine hydrochloride (Example the title compound was prepared as a white solid (melting point 139-14 1 Purification was by flash chromatography eluting with CH 2
CI
2 /EtOAc Rr -0.46 (CH 2 Cl 2 /EtOAc, 1:1).
C
32
H
26
F
2
N
4 0 4 (MW 568.59); mass spectroscopy (MN 569.2 (MN-) 567.4.
Anal. Calcd. for C 32
H
26
F
2
N
4 0 4 C, 67.60; H, 4.61; N, 9.85. Found: C, 67.39; H, 4.66; N, 9.60.
WO 98t28268 PCT/US97/22986 399 Example 8-164 Synthesis of 3-[N'-(Cyclopentylacetyl)-L-alaninyllamino-2,4-dioxol,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazep'ine Following General Procedure I above using cyclopentylacetic acid (Aldrich) and 3-(L-alaninyl)-amino-2 ,4-dioxo- 1, 5-bis-phenyl-2 5-tetrahydro-l1H- benzodiazepine hydrochloride (Example the title compound was prepared as an amorphous white solid. Purification was by flash chromatography eluting with CH 2 Cl 2 /EtOAc Rf 0.44 (CH 2
CI
2 /EtOAc, 1: 1).
C
31 H1 32
N
4 0 4 (MW 524.63); mass spectroscopy 525.2 523.2.
Anal. Calcd. for C 3 1
H
32
N
4 0 4 C, 70.97; H, 6.15; N, 10.68. Found: C, 70.67; H, 5.98; N, 10.43.
Example 8-165 Synthesis of 3-[N'-(Cyclopentyl-oe-hydroxyacetyl)-L-alaninyI]-amino- 2,4-dioxo-1 ,5-bis-phenyl-2,3,4,5- Following General Procedure I above using cyclopentyl-ae-hydroxyacetic acid (Example P) and 3-(L-alaninyl)-amino-2,4-dioxo-1 ,5-bis -phenyl-2,3,4,5tetrahydro-1H-1 ,5-benzodiazepine hydrochloride (Example the title compound was prepared as a white solid (melting point 139-149'C).
Purification was by flash chromatography eluting with CH 2 Cl 2 /EtOAc Rf =0.50 and 0.39 (CH 2 Cl 2 /EtOAc, 1:2).
C
31
H
32
N
4 0 5 (MW 540.63); mass spectroscopy 541.2 539.6.
Anal. Calcd. for C 3 1
H
32
N
4 0 5 C, 68.87; H, 5.97; N, 10.36. Found: C, 68.87; H, 5.88; N, 10. Example 8-166 Synthesis of 3-(N'-(3,5-Difluorophenylacetyl)-L-alaninyl)amiino- 2 ,3-dihydro-1-methyl-5-phenyl-1H- 1,4-benzodiazepin-2-one Following General Procedure A above using L-alanine (Example B) and 3-amino-2,3-dihydro-l-methyl-5-phenyl-1H-1 ,4- WO 98/28268 PCT/US97/22986 400 benzodiazepin-2-one (prepared as described in Bock M. DiPardo, R. M.; Evans, B. Rittle, K. Veber, D. Freidinger, R. Hirshfield, J.; Springer, J. P. J. Org. Chem. 1987, 52, 3232), the title compound was prepared as a solid having a melting point of 152-160 0 C. The reaction was monitored by tic on silica gel (Rf 0.15 in 50% ethyl acetate/hexanes) and purification was by silica gel chromatography.
NMR data was as follows: 'H-nmr (CDC13): 6 7.70 J=7.2, 7.2, 1H); 7.4 9H); 6.83 (d, 2H); 6.7 1H); 6.50 J=7.1, 1H); 5.44 (dd, 2.8, 4.9, 2.8, 1H); 4.7 1H); 3.53 2H); 3.45 3H); 1.46 (dd, J=4.4, 2.2, 4.9, 3H).
"C-nmr (CDCl 3 6 172.9, 167.8, 138.3, 133.4, 127.7, 126.5, 126.3, 125.4, 123.9, 120.3, 117.2, 108.1, 107.8, 98.4, 63.0, 44.7, 40.1, 38.4, 30.9, 14.5, 14.1.
C
2 7H 24
F
2
N
4 0 3 (MW 490); mass spectroscopy 491.
The title compound was resolved using a Daicel chiral column (2 x 25 cm, ID x L) (normal phase polysaccharide type; 10 micro particle size). Using a gradient of 40% isopropanol/hexanes (4 mL/min flow rate for 35 minutes), followed by 20% isopropanol/hexanes (3 mL/min), isomer 1 and isomer 2 had retention times of 27.5 and 36.4 minutes, respectively.
Example 8-167 Synthesis of 3-(N'-(3,5-Difluorophenyl-a~-hydroxyacetyl)-L-alaninyl)amino- 5H-pyrrolo[1,2-a][1,5]benzodiazepin-6(7H)-one 5H-Pyrrolo[1,2-a][1,5]benzodiazepin-6(7H)-one (CAS No. 63743-03-3) was methylated using General Procedure 8-I, aminated by azide transfer using General Procedure 8-D and azide reduction using General Procedure 8-F, and coupled to L-Boc-alanine (Sigma) using General Procedure D. The Boc group was then removed using General Procedure 8-N and the diastereomers were separated by LC chromatography. Each isomer was separately coupled with WO 98/28268 PCT/US97/22986 401 acid (Example L) using General Procedure D to give the title compound.
Isomer 1: Melting point 239-240*C.
MW 469.1687; exact mass spectroscopy 469.1693.
Optical rotation: -121.18° 589 and -540.33° 365 (c =1, MeOH).
Isomer 2: Melting point 144-145*C.
MW 469.1687; exact mass spectroscopy 469.1687.
Optical rotation: +64.66° 589 and +255.030 365 (c =1, MeOH).
Using the following combinatorial procedures, the following additional intermediates and examples were prepared.
GENERAL PROCEDURE C-A To a 4 mL vial containing 60-100 mg (0.06-0.1 mmol) of polymer bound 1-(1-pyrrolidinyl propyl)-3-ethyl carbodiimide was added 2 mL of a 0.015 mM stock solution of starting material 1 in DMF/chloroform and 1 mL of a 0.0148 mM stock solution of starting material 2 in chloroform. The resulting slurry were shaken for 48 h and filtered. The filtered resin was washed with chloroform and the filtrate was concentrated to dryness under vacuum. All product structures and purities were confirmed by HPLC using UV detection and IEX MS. Samples were submitted for testing with out any further purification.
GENERAL PROCEDURE C-B To a 4 mL vial was added 840 uL of 0.05 mM stock solution of starting material 1 in DMF/chloroform, 100 uL of a 0.21 mM stock solution of starting material 2 in chloroform and 100 uL of a 0.63 mM stock solution of 1-(3- WO 98/28268 PCT/US97/22986 402 dimethylaminopropyl)-3-ethyl carbodiimide in chloroform. After allowing to stand undisturbed for 48 h, the reaction mixture was concentrated and the residue redissolved in 2 mL of a 10% methanol/methylene chloride solution.
This solution was then filtered through a pre-washed (methanol) 500 mg SCX column (Varian Sample Preparation; Harbor City California) using an additional 8 mL of the same solvent. The filtrate was concentrated under reduced pressure and the residue was dissolved in 20% methanol/methylene chloride and passed through a plug of silica gel (100 mg, Varian Sample Preparation). The collected filtrate was concentrated under reduced pressure and the crude products were submitted for testing without further purification.
Product structure and purity were confirmed by HPLC and IEX MS.
GENERAL PROCEDURE C-C To a 4 mL vial was added 540 uL of 0.05 mM stock solution of starting material 1 in DMF/chloroform, 100 uL of a 0.44 mM stock solution of starting material 2 in chloroform and 100 uL of a 0.38 mM stock solution of 1-(3dimethylaminopropyl)-3-ethyl carbodiimide in chloroform. After standing undisturbed for 48 h, the reaction mixture was concentrated and the residue redissolved in 2 mL of a 10% methanol/methylene chloride solution. This solution was then filtered through a pre-washed (methanol) 500 mg SCX column using an additional 8 mL of the same solvent. The filtrate was concentrated under reduced pressure and the residue was dissolved in methanol/methylene chloride and passed through a plug of silica gel (100 mg, Varian Sample Preparation). The collected filtrate was concentrated under reduced pressure and the crude products were submitted for testing without further purification. Product structure and purity were confirmed by HPLC and IEX MS.
GENERAL PROCEDURE C-D To a 4 mL vial was added 540 uL of 0.05 mM stock solution of starting material 1 in DMF chloroform, 100 uL of a 0.44 mM stock solution of WO 98/28268 PCTIUS97/22986 403 starting material 2 in chloroform, 100 uL of a 0.38 mM stock solution of 1-(3dimethylaminopropyl)-3-ethyl carbodiimide in chloroform and 100 uL of a 0.38 mM stock solution of PP-HOBt in DMF. After standing undisturbed for 48 h, the reaction mixture was concentrated and the residue redissolved in 2 mL of a 10% methanol/methylene chloride solution. This solution was then filtered through a pre-washed (methanol) 500 mg SCX column using an additional 8 mL of the same solvent. The filtrate was concentrated under reduced pressure and the residue was dissolved in 20% methanol/methylene chloride and passed through a plug of silica gel (100 mg, Varian Sample Preparation). The collected filtrate was concentrated under reduced pressure and the crude products were submitted for testing without further purification. Product structure and purity were confirmed by HPLC and IEX MS.
GENERAL PROCEDURE C-E To a 4 mL vial was added 870 uL of 0.05 mM stock solution of starting material 1 in DMF/chloroform, 1000 uL of a 0.05 mM stock solution of starting material 2 in chloroform, 1000 uL of a 0.05 mM stock solution of 1-(3dimethylaminopropyl)-3-ethyl carbodiimide in chloroform and 100 uL of a 0.48 mM stock solution of HOBt in DMF. After standing undisturbed for 48 h, the reaction mixture was concentrated and the residue redissolved in 2 mL of a methanol/methylene chloride solution. This solution was then filtered through a pre-washed (methanol) 500 mg SCX column using an additional 8 mL of the same solvent. The filtrate was concentrated under a stream of nitrogen to approximately 1/3 its original volume and then passed over a plug (200 mg) of AG 1-8x anion exchange resin (BioRad; Hercules, California; Columns were pre-washed with 1N NaOH, water and methanol) using an additional 6 mL of 10% methanol/methylene chloride solution. The resulting filtrate was concentrated under vacuum and the crude products were submitted for testing without further purification. Product structure and purity were confirmed by HPLC and IEX MS.
WO 98/28268 PCT/US97/22986 404 GENERAL PROCEDURE C-F Starting material 1 (9.1 uL, 0.109 mmol) was added neat to a mixture of starting material 2 (22.5 mg, 0.054 mmol) and piperidinylmethyl polystyrene mg, 3.6 mmol/g (Fluka)) in 1 mL of methylene. The mixture was shaken for 80 h at ambient temperatures and then treated with methylisocyanate polystyrene (100 mg, 1.0 mmol/g (Novabiochem)) for 24 h with shaking. The reaction mixture was filtered and the resin washed with methylene chloride.
The crude product was loaded onto a 500 mg SCX ion exchange column (Varian Sample Preparation), washed 3X with 3 mL of methanol and then eluted with 4 mL of 2 M ammonia methanol. Further purification of the final product was achieved using semi-preparative HPLC (0-100% acetonitrile (0.08 TFA)/water (0.1 TFA); 25 mL/min.; 20X50 ODS-A column) to give 17 mg of the final product as an off white foam.
NMR data was as follows: 'H NMR (300 MHz, CDCl 3 6 1.45-1.65 3 1.70-2.00 4 H), 2.55-2.80 4 3.25 2 3.50 3H), 4.65-4.80 1 5.45-5.55 1 7.20-7.80 11 H).
*GENERAL PROCEDURE C-G To a 4 mL vial containing 0.03 mmol of starting material 2 was added 100 uL of 0.25 mM stock solution of starting material 1 in chloroform, 100 uL of a 0.3 mM stock solution of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide in chloroform and 100 uL of a 0.3 mM stock solution of HOBt in DMF. After standing undisturbed for 48 h, the reaction mixture was concentrated and the residue redissolved in 2 mL of a 10% methanol/methylene chloride solution.
This solution was then filtered through a pre-washed (methanol) 500 mg SCX column using an additional 8 mL of the same solvent. The filtrate was concentrated under a stream of nitrogen to approximately 1/3 its original volume and then passed over a plug (200 mg) of AG 1-8x anion exchange resin (BioRad; Hercules, California; Columns were pre-washed with IN NaOH, water and methanol) using an additional 6 mL of 10% methanol/methylene WO 98/28268 PCT/US97/22986 405 chloride solution. The resulting filtrate was concentrated under vacuum and the crude products were submitted for testing without further purification. Product structure and purity were confirmed by HPLC and IEX MS.
GENERAL PROCEDURE C-H The intermediates shown in Table C-l Starting material 2) were synthesized in parallel in using the following procedure: Step A: To a solution of 3-(tert-butoxycarbonyl)amino-2,3-dihydro-5phenyl-lH-1,4-benzodiazepin-2-one (CA No. 125:33692: 100 mg, 0.28 mmol) in 1 mL of anhydrous DMF was added 600 uL of a solution of 0.5 M potassium bis(trimethylsilyl)amide (0.30 mmol) in toluene. Neat alkyl halide (0.56 mmol; as indicated in Table C-1) was added immediately in one portion and the reaction mixture was left undisturbed overnight. When an alkyl chloride was used, 1 equivalent of sodium iodide was added to the reaction mixture. After concentration under reduced pressure, the crude reaction residue was partitioned between methylene chloride (2 mL) and aqueous saturated bicarbonate (2 mL) and then passed through a 5 g Extralut QE cartridge (EM Science; Gibbstown, NJ) using 10 mL of methylene chloride.
The resulting filtrate was concentrated under reduced pressure and the crude product was further purified using automated semi-preparative HPLC (YMC X 50 mm Silica column; gradient elution; 0-5 (5.5 min.), 5-20 min.), 20-100 (2 min.), 100% (4 min.) ethyl acetate/methylene chloride, flow rate of 25 mL/min.). Product provided the expected M+1 peak by IEX MS and were carried on without further purification and characterization.
Step B: The product obtained from Step A was dissolved in 5 mL of a TFA/methylene chloride solution and allowed to stand undisturbed for 16 h.
After concentration under reduced pressure, the TFA salt was dissolved in methanol and loaded directly onto a 1 g SCX column. The column was washed 3 X with 2 mL portions of methanol and the product was eluted from the column using 6 mL of 2.0 M solution of ammonia/methanol. After WO 98/28268 PCTI~S97298 406 concentration under reduced pressure, the product were characterized by IEX MS and carried on without further purification.
Step C: To the crude product obtained from Step B (1.05 equiv.) was added sequentially a 0.3 mM stock solution of HOBtH 2 0O (1.05 equiv.) in DMF, a 0.3 mM stock solution of N-t-BOC-L-alanine (1.0 equiv.) in THF and 0.3 mM stock solution of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (1.05 equiv.) in THF. After standing undisturbed for 24 h, the reaction mixture was concentrated and the residue redissolved in 2 mL of a 10% methanol/methylene chloride solution. This solution was then filtered through a pre-washed (methanol) 1 g SCX (Varian Sample Preparation) column using an additional 8 mL of the same solvent. For Example C-V a 1 g Si column (Varian Sample Preparation) was used). The filtrate was concentrated under a stream of nitrogen to approximately 1/3 its original volume and then passed over a plug (500 mg) of AG 1-8x anion exchange resin (BioRad; Hercules, California; Columns were pre-washed with 1N NaOH, water and methanol) using an additional 10 mL of methanol. The resulting filtrate was concentrated under reduced pressure and the crude product was carried on without further purification after characterization by IEX MS.
Step D: The crude product obtained from Step C was dissolved in 5 mL of a 15 TFA/methylene chloride solution and allowed to stand undisturbed for 16 h. After concentration under reduced pressure, the TFA salt was dissolved in methanol and loaded directly onto a 1 g SCX column. The column was washed 3 X with 2 mL portions of methanol and the product were eluted from the column using 6 mL of 2.0 M solution of ammonia/methanol. After concentration under reduced pressure, the product were characterized by IEX MS and carried on without further purification. The intermediates prepared by this method are shown in Table C-A.
WO 98/28268 PC2TIUS97/22986 407 TABLE C-A Intermediates Ex. Alkyl Halide JIntermediate
IMS
C-A 3-Fluorobenzyl bromide 3 -(L-alaninyl)amino-5-phenyl- 431.1 (Aldrich) 2,3-dihydro- 1-(3-fluorobenzyl)- 1H-i ,4-benzodiazepin-2 -one C-B Benzyl bromide 3 -(L-alaninyl)amino-5-phenyl- 513.2 (Aldrich) 2, 3-dihydro-l1-(benzy 1)-iH- 1,4- C-C tert-Butylbenzyl bromide 3 -(L-alaninyl)amino-5-phenyl- 469.2 (Aldrich) 2, 3-dihydro-l1-(4-tertbutylbenzyl)-1H-1 ,4- _______benzodiazepin-2-one C-D 2-Bromoethylcyclohexane 3 -(L-alaninyl)amino-5-phenyl- 433.2 (Fairfield) 2, 3-dihydro-l1-(2cyclohexylethyl)-l1H- 1,4benzodiazepin-2-one C-E 1 -Bromo-3 ,3-dimethylbutane 3-(L-alaninyl)amino-5-phenyl- 407.2- (Wiley) 2, 3-dihydro-l1-(3,3dimethylbutyl)-l1H- 1,4benzodiazepin-2-one C-F Methyl alpha- 3-(L-alaninyl)arnino-5-phenyl- 471.2 bromophenylacetate 2 ,3-dihydro-l1-(1- (Aldrich) methoxycarbonyl- 1phenylmethy 1)-iH- 1,4- C-G 1-bromo-2-ethylbutane 3-(L-alaninyl)amino-5-phenyl- 407.2 (Aldrich) 2, 3-dihydro-l1-(2-ethylbutyl)- 1H- 1 ,4-benzodiazepin-2-one C-H Bromomethylcyclohexane 3-(L-alaninyl)amino-5-phenyl- 419.2 (Aldrich) 2,3-dihydro- 1- (cyclohexylmethyl)- 1H-1 ,4- C-I 2-(Bromoethyl)benzene 3 -(L-alaninyl)amino-5-phenyl- 427.2 (Aldrich) 2, 3-dihydro-l1-(2-phenylethyl)- 1 H-i ,4-benzodiazepin-2-one C-J 3-(Bromopropyl)benzene 3-(L-alaninyl)amino-5-phenyl- 441.2 (K and K Laboratories) 2,3-dihydro-1-(3-phenylpropyl)- 1 H-i ,4-benzodiazepin-2-one WO 98/28268 PCT/US97t22986 408 Ex. Alkyl Halide IIntermediate I MS C-K 3-(L-alaninyl)amino-5-phenyl- 496.2 Bromoethyl)phthalimide 2 ,3-dihydro- (Aldrich) phthalimidyl)ethyl)-1H-1 ,4- _______benzodiazepin-2-one C-L 2-Phenylbenzyl bromide 3-(L-alaninyl)amino-5-phenyl- 489.2 (Aldrich) 2 ,3-dihydro-1 biphenylmethyl)- lH- 1,4- C-M Tetrahydrofuirfuryl bromide 3-(L-alaninyl)amino-5-phenyl- 407.2 (Lancaster) 2, 3-dihydro-l1-((2tetrahydrofuranyl)methyl)-l1H- 1 ,4-benzodiazepin-2-one C-N 2-Bromomethyl-i 3-(L-alaninyl)amino-5-phenyl- 471.2 benzodioxane 2,3-dihydro-i-(2-(1 ,4- (Acros) benzodioxanyl)methyl)-l1H- 1,4- C-0 3-Bromomethyl-5- 3-(L-alaninyl)amino-5-phenyl- 503.1 chlorobenzo[b]thiophene 2, 3-dihydro-l1-((3-(5- (Maybridge) chlorobenzo[bI thienyl))methyl)- 1 H-i ,4-benzodiazepin-2-one c-P 1 -Bromopinacolone 3-(L-alaninyl)amino-5-phenyl- 421.1 (Lancaster) 2,3 -dihydro-l1-(3, 3-dimethyl-2oxo-propyl)- 1H- 1,4benzodiazepin-2-one C-Q 5- 3-(L-alaninyl)amino-5-phenyl- 455.2 (Bromomethyl)benzofurazan 2, 3-dihydro- (Maybridge) benzofuirazanylmethyl)-l1H-i .4- C-R 3-Phenoxypropyl bromide 3-(L-alaninyl)amino-5-phenyl- 457.2 (Aldrich) 2, 3-dihydro-l1-(3-phenoxypropyl)- 1 H-i ,4-benzodiazepin-2-one C-S 6-(Bromomethyl)-2- 3-(L-alaninyl)amino-5-phenyl- 533.2 (trifluoromethyl)quinoline 2, 3-dihydro-l1-(6-(2- (Maybridge) trifluoromethylquinolinyl)methyl) 1H-1 ,4-benzodiazepin-2-one C-T 1-bromo-2-methylbutane 3-(L-alaninyl)amino-5-phenyl- 393.2 (Aldrich) 2, 3-dihydro-l1-(2-methylbutyl)- 1 H-i ,4-benzodiazepin-2-one C-U Ethyl bromide 3-(L-alaninyl)amino-5-phenyl- 351.2 (Aldrich) 2, 3-dihydro- 1 -(ethyl)- 1 H- 1,4- WO 98/28268 PCT/US97/22986 409 Ex. Alkyl Halide Intermediate
MS
C-V 3-Picolyl chloride 3 -(L-alaninyl)amino-5-phenyl- 414.1 hydrochloride 2,3-dihydro-1--(3-pyridylmethyl)- (Aldrich) 1H-1,4-benzodiazepin-2-one C-W 1-(2-Chloroacetyl)indoline 3-(L-alaninyl)amino-5-phenyl- 482.2 (Maybridge) 2,3-dihydro-l-(2-oxo-2-(Nindolinyl)ethyl)-lH-1,4benzodiazepin-2-one C-Y 4-(Chloromethyl)-3,5- 3-(L-alaninyl)amino-5-phenyl- 432.2 dimethylisoxazole 2,3-dihydro-l-((4-(3,5- (Aldrich) dimethyl)isoxazolyl)methyl)-lH- 1,4-benzodiazepin-2-one.
C-Z 2-Bromoethyl methyl ether 3-(L-alaninyl)amino-5-phenyl- 381.2 (Aldrich) 2,3-dihydro-l-(2-methoxyethyl)- 1H-1,4-benzodiazepin-2-one GENERAL PROCEDURE C-I To a 4 mL vial containing 0.03 mmol of starting material 2 (from General Procedure C-H) was added 100 uL of 0.25 mM stock solution of starting material 1 in chloroform, 100 uL of a 0.3 mM stock solution of 1-(3dimethylaminopropyl)-3-ethyl carbodiimide in chloroform and 100 uL of a 0.3 mM stock solution of HOBt in DMF. After standing undisturbed for 48 h, the reaction mixture was concentrated and the residue redissolved in 2 mL of a methanol/methylene chloride solution. This solution was then filtered through a pre-washed (methanol) 500 mg Si column using an additional 8 mL of the same solvent. The filtrate was concentrated under a stream of nitrogen to approximately 1/3 its original volume and then passed over a plug (200 mg) of AG 1-8x anion exchange resin (Columns were pre-washed with 1N NaOH, water and methanol) using an additional 6 mL of 10% methanol/methylene chloride solution. The resulting filtrate was concentrated under vacuum and the crude products were submitted for testing without further purification. Product structure and purity were confirmed by HPLC and IEX MS.
WO 98/28268 PCTUS97I22986 410 Example C-AA Synthesis of (S)-3-(L-phenylglycinyl)amino- 2,3-dihydro-l-methyl-5-phenyl-lH-1 ,4-benzodiazepin-2-one Step A: Synthesis of (S)-3-(N'-(tert-Butoxycarbonyl)-Lphenylglycinyl)amino-2,3-dihydro-1-methyl-5phenyl-1H-1 ,4-benzodiazepin-2-one To a solution of triethyl amine (519 uL, 3.8 mmol) and phenyl-2-oxo-1 ,4-benzodiazepine (1.0 g, 3.8 mmol) (prepared according to the procedure of M. G. Bock et al., J. Org. Chem. 1987, 52, 3232-3239) in 100 mL of anhydrous methylene chloride at -20'C was added N-Boc-Lphenyiglycine fluoride (Carpino et al, J. Org. Chem. 1991, 56, 2611-2614) in one portion. The reaction mixture was stirred for 15 min. and quenched with saturated aqueous bicarbonate (10 mL). The layers were seperated, the organic layer washed sequentially with saturated aqueous bicarbonate, water and brine and then dried over sodium sulfate. Purification of the crude product using silica gel chromatography (10-50% ethyl acetate hexane) gave 1.3 g of a hydroscopic white foam.
NMR data was as follows: 'H NMR (300 MHz, CDCl 3 6 =1.35 (br s, 9H), 3.41 3H), 5.30-5.45 (in, 2H), 5.75-5.95 (in, 1H), 7.15-7.75 (mn, 1511).
IR (CDCl 3 1709.7, 1676.6, 1489, 1166.3 cm- 1 IEX MS (M 498. 0.
Step B: Synthesis of (S)-3-(L-phenylglycinyl)amino-2,3dihydro-l-methyl-5-phenyl-1H-1 ,4-benzodiazepin-2one '-(tert-Butoxycarbonyl)-L-phenylglycinyl)anino-2 ,3-dihydro- 1 methyl-5-phenyl-1H-1 ,4-benzodiazepin-2-one (1.27 g, 2.55 inmol) was added to 50 mL of a stirring solution of 15 TFA in methylene chloride in one portion.
After stirring 1 h, the reaction mixture was concentrated under reduced pressure and the residue dissolved in 100 mL of methylene chloride. This solution was washed twice with saturated sodium bicarbonate, once with brine WO 98/28268 PCT/US9/298 411and then dried over sodium sulfate. Purification of the crude product using silica gel column chromatography (5-10% methanol/methylene chloride) gave 743 mg of a very light green foam.
NMR data was as follows: 'H NMR (CDCl 3 6 2.05 (br s, 1 3.45 3 5.51 J 8.39 Hz, 1H), 7.15-7.70 14 8.60 J 830 Hz, 1 H).
IR (CDCl 3 1673.3, 1601.1, 1506.1 cm-'.
IEX MS 399.2.
Example C-AB Synthesis of 3-(L-Alaninyl)amino-2,3-dihydro-1- (2-oxo-2-phenylethyl)-5-phenyl-1H-1,4-benzodiazepin-2-one Step A: Synthesis of 3-(Benzoxycarbonyl)amino-2,3dihydro-l-(2-oxo-2-phenylethyl)-5-phenyl-lH-1,4benzodiazepin-2-one To a solution of 3-(Benzoxycarbonyl)amino-2,3-dihydro-5-phenyl- H-1,4benzodiazepin-2-one (Bock, M. G. et al, Tetrahedron Lett. 1987, 28, 939; g, 10.4 mmol) in 40 mL of anhydrous DMF at 0°C was added potassium tertbutoxide (1.51 g, 13.5 mmol) in one portion. The reaction mixture was stirred min. and a-bromoacetophenone (Lancaster; Windham, NH; 2.9 g, 14.6 mmol) was added. The reaction mixture was warmed to room temperature over min. and then diluted with 100 mL of water and 200 mL of methylene chloride. The layers were separated. The organic layer was extracted with water and dried over sodium sulfate. Purification of the crude product by silica gel column chromatography ethyl acetate/methylene chloride) gave 4.2 g of an off white foam.
NMR data was as follows: 'H NMR (300 MHz, CDCl 3 6 5.16 2 5.34 2 5.50 J 8.33 Hz, 1 6.70 J 8.28 Hz, 1 7.20-7.70 12 7.91 J 7.54 Hz, 2 H).
IR (CHCl 3 1706.04, 1685.3, 1505.9, 1489.1, 1450.3, 1244.7 cm-'.
IEX MS 504.3.
WO 98/28268 PCT/US97/22986 412 Step B: Synthesis of 3 -Amino-2,3-dihydro-1-(2-oxo-2phenylethyl)-5-phenyl-1H-1,4-benzodiazepin-2-one A solution of 3-(Benzoxycarbonyl)amino-2,3-dihydro-l-(2-oxo-2phenylethyl)-5-phenyl-1H-1,4-benzodiazepin-2-one (3.7 g, 7.36 mmol) in 100 mL of anhydrous methylene chloride was cooled to 0°C under nitrogen. A stream of anhydrous HBr gas was then bubbled through this solution for 1 h.
The bubbler was removed and the reaction was warmed to room temperature under nitrogen. After stirring 1 h the reaction was concentrated under vacuum and the residue was redissolved in 20 mL of methylene chloride. The crude HBr salt of the product was precipitated from solution using 300 mL of anhydrous ether and collected by filtration as a light yellow solid. After washing with ether the solid was dissolved in methylene chloride and saturated sodium bicarbonate. The layers were separated and the organic layer was extracted with saturated sodium bicarbonate. The combined aqueous layers were then back extracted twice with methylene chloride. The combined organic layers were extracted once with water and dried over sodium sulfate. After concentration under vacuum, 2.27 g of the product was obtained as an orange foam which was carried on without further purification.
NMR data was as follows: 'H NMR (300 MHz, CDCl 3 6 2.60 (br s, 2 4.72 1 5.34 (s, 2 7.10-7.70 12 7.91 J 7.60 Hz, 2 H).
IEX MS 370.2 Step C: Synthesis of 3-(N'-(tert-Butoxycarbonyl)-Lalaninyl)amino-2,3-dihydro-l-(2-oxo-2-phenylethyl)- 5-phenyl-1H-1,4-benzodiazepin-2-one To a solution of HOBt-H 2 0 (697 mg, 5.16 mmol), N,Ndiisopropylethylamine (900 uL, 5.16 mmol) and N-t-BOC-L-alanine (975 mg, 5.16 mmol) in 20 mL of anhydrous THF at 0°C was added 1-(3dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI; 986 mg, 5.16 mmol) in one portion. After stirring 5 min., a solution of 3-amino-2,3-dihydro- 1-(2-oxo-2-phenylethyl)-5-phenyl-lH-1,4-benzodiazepin-2-one (2.0 g, 5.43 WO 98/28268 PCT1US97t22986 413 mmol) in 20 mL of anhydrous THF was added via syringe and the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with 200 mL methylene chloride, extracted sequentially with 10 citric acid, saturated sodium bicarbonate, water and brine and then dried over sodium sulfate. Purification of the crude product using silica gel chromatography (10%-30% ethyl acetate/methylene chloride) gave 2.59 g of a white foam.
NMR data was as follows: 'H NMR (300 MHz, CDC1 3 6 1.30-1.60 12 4.35 (br s, 1 H), 5.00-5.50 3 5.65-5.70 1 7.15-7.65 12 7.70-7.80 1 7.85-7.95 1 H).
IR (CHCI3): 1705.8, 1678.8, 1488.7, 1450.2, 1230.4, 1164.4 cm-'.
IEX MS 541.2.
Step D: Synthesis of 3-(L-Alaninyl)amino-2,3-dihydro-1-(2oxo-2-phenylethyl)-5-phenyl-1H-1,4-benzodiazepin- 2-one 3-(N'-(tert-Butoxycarbonyl)-L-alaninyl)amino-2,3-dihydro-l-(2-oxo-2phenylethyl)-5-phenyl-lH-1,4-benzodiazepin-2-one (2.5 g, 4.63 mmol) was added to 100 mL of a stirring solution of 15 TFA/methylene chloride in one portion. After stirring 2 h, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in 150 mL of methylene chloride. This solution was washed twice with saturated sodium bicarbonate, once with brine and then dried over sodium sulfate. Purification of the crude product using silica gel column chromatography (1-10% methanol/methylene chloride) gave 1.91 g of the title compound as a white foam.
NMR data was as follows: 'H NMR (300 MHz, CDCI 3 6 1.30-1.50 3 1.80-2.20 (br s, 2 3.55-3.75 1 5.20-5.45 2 5.67 J 7.48 Hz, 1 7.20- 7.65 12 7.90 J 7.7 Hz, 2 8.80 (dd, J 1 25.09 Hz, Jz 8.33 Hz, 1 H).
EX MS 441.2.
WO 98/28268 PTU9/28 414-- Example C-AC Synthesis of 3-(L-Alaninyl)amino-2,3-dihydro-1- (4,4,4-trifluorobutyl)-5-phenyl-1H- 1,4-benzodiazepin-2-one Step Synthesis of 3-(BenzoxycarbonyI)amino-2,3-dihydro-l-.
(4,4,4-trifluorobutyl)-5-phenyl-1H-1 ,4-benzodiazepin-2-one To a solution of 3-(benzoxycarbonyl)amino-2 ,3-dihydro-5-phenyl-l1H- 1,4benzodiazepin-2-one (3.7 g, 9.61 mmol) in 40 mL of anhydrous DMF at 0 0
C
was added potassium tert-butoxide (1.6 g, 14.4 mmol) in one portion. The reaction mixture was stirred 20 min. and 4 ,4,4-trifluoro-1-bromobutane (Lancaster; Windham, NH; 2.6 g, 13.4 mmol) was added. The reaction mixture was warmed to room temperature over 30 min. and then diluted with 100 mL of water and 200 mL of methylene chloride. The layers were separated. The organic layer was extracted with water and dried over sodium sulfate. Purification of the crude product by silica gel column chromatography (0-3 ethyl acetate methylene chloride) gave 1.52 g (32 of an off white foam.
NMR data was as follows: 'H NMR (300 MHz, CDC1 3 6 1.50-2. 10 (in, 4 3.70-3.90 (mn, 1 4.35-4.55 (in, 1 5.15 2 5.33 J 8.47 Hz, 1 6.67 J 8.40 Hz, 1 7.2-7.70 (in, 14 H).
IR (CHC1 3 1720.4, 1683.0, 1604.8, 1505.5, 1451.1, 1323.9, 1254.5, 1148.4 cm-'.
TEX MIS (M 496.3.
Step B: Synthesis of 3-Amino-2,3-dihydro-1-(4,4,4-trifluorobutyl)- 5-phenyl-1H-1 ,4-benzodiazepin-2-one A solution of 3-(benzoxycarbonyl)amino-2 ,3-dihydro- 1-(4,4,4trifluorobutyl)-5-phenyl-1H-1,4-benzodiazepin-2-one (1.42 g, 2.87 inmol) in mL of anhydrous mnethylene chloride was cooled to 0*C under nitrogen. A stream of anhydrous HBr gas was slowly bubbled through the solution for 1 h.
The bubbler was removed and the reaction was warmed to room temperature under nitrogen. After stirring for 1 h, the reaction was concentrated under WO 98/28268 PCTfUS97/22986 415 vacuum and the residue was redissolved in 10 mL of methylene chloride. The crude HBr salt of the product was precipitated from solution using 90 mL of anhydrous ether and collected by filtration. After washing with ether, the HBr salt was dissolved in methylene chloride and saturated sodium bicarbonate.
The layers were separated and the organic layer was extracted with saturated sodium bicarbonate. The combined aqueous layers were then back extracted twice with methylene chloride. The combined organic layers were extracted once with water and dried over sodium sulfate. After concentration under vacuum, 1.06 g (100%) of the product was obtained as a white foam which was carried on without further purification.
NMR data was as follows: 'H NMR (300 MHz, CDCl1): 6 1.60-2.10 4 2.76 (br s, 2 H), 3.75-3.85 1 4.40-4.60 2 7.20-7.70 9 H).
IEX MS 362.1.
Step C: Synthesis of 3-(N'-(tert-Butoxycarbonyl)-L-alaninyl)amino- 2,3-dihydro-1-(4,4,4-trifluorobutyl)-5-phenyl-1H-1,4benzodiazepin-2-one To a solution of HOBt-H 2 0 (373 mg, 2.76 mmol), N,Ndiisopropylethylamine (481 uL, 2.76 mmol) and N-t-BOC-L-alanine (522 mg, 2.76 mmol) in 10 mL of anhydrous THF at 0°C was added 1-(3dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI; 527 mg, 2.76 mmol) in one portion. After stirring 5 min., a solution of 3-amino-2,3-dihydro- 1-(4,4,4-trifluorobutyl)-5-phenyl-1H-1,4-benzodiazepin-2-one (1.05 g, 2.91 mmol) in 10 mL of anhydrous THF was added via syringe and the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with 100 mL methylene chloride, extracted sequentially with 10% citric acid, saturated sodium bicarbonate, water and brine and then dried over sodium sulfate. Purification of the crude product using silica gel chromatography (10%-30% ethyl acetate/methylene chloride) gave 1.28 g of a white foam.
NMR data was as follows: WO 98/28268 PTU9/28 PCTfUS97/22986 416-- 'H NMR (300 MHz, CDC1 3 b 1.40-2. 10 (in, 16 3.70-3.85 (in, 1 4.30-4.55 (mn, 2 5. 10 (br s, 1 5.45-5.55 (mn, 1 7.25-7.80 (mn,
H).
IR (CDCl 3 1676.6, 1605.2, 1488.6, 1450.9, 1393.2, 1338.7, 1324.9, 1253.8, 1150.4 cm-1.
TEX MS (M 533. 1.
Step D: Synthesis of 3-(L-Alaninyl)amino-2,3-dihydro-1-(4,4,4trifluorobutyl)-5-phenyl-1H-1 ,4-benzodiazepin-2-one 3-(N -(tert-Butoxycarbonyl)-.L-alaninyl)amino-2 ,3-dihydro-l1-(4,4,4trifluorobutyl)-5-phenyl-LH-1 ,4-benzodiazepin-2-one (1.21 g, 2.27 inmol) was added to 50 mL of a stirring solution of 15 TFA methylene chloride in one portion. After stirring 2 h, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in 100 mL of methylene chloride. This solution was washed twice with saturated sodium bicarbonate, once with brine and then dried over sodium sulfate. Purification of the crude product using silica gel column chromatography (1 -5 methanol methylene chloride) gave 670 mng of a light pink foam.
NMR data was as follows: 'H NMR (300 MHz, CDCl 3 b 1.43 J 7.0 Hz, 3 1.60-2.20 (in, 7 3.60-3.85 (in, 2 4.35-4.55 (in, 1 5.51 (dd, J, 8.36 Hz, J 2 2.48 Hz, 1 7.20-7.70 (in, 9 8.80 (dd, J, 27.73 Hz, J 2 8.34 Hz, 1 H).
IEX MS (M 433.2.
Example C-AD Synthesis of 3-(N'-(Chloroacetyl)-L-alaninyl)amino-2,3-dihydro- 1H-1,4-benzodiazepin-2-one A solution of 3-(L-alaninyl)amino-2,3-dihydro-1-nethyl-5-phenyl-1H-1 ,4benzodiazepin-2-one (20.0 mng, 0.0595 inmol), ci-chloroacetyl chloride (5.9 uL, 0.0744 imol) and piperidinylinethyl polystyrene (59.5 ing, 3.6 inmol/g WO 98/28268 PCTIUS97/22986 417 (Fluka)) in 1 mL of methylene chloride were shaken for 20 min. Aminomethyl polystyrene (58 mg, 3.0 mmol/g (Advanced Chemtech)) was then added and the reaction mixture was shaken for an additional 15 min. and filtered. Removal of the solvent under reduced pressure provided 23.9 mg of the crude product which was used without further purification.
NMR data was as follows: 'H NMR (300 MHz, CDCl 3 6 1.40-1.60 3 3.40-3.6 3 H), 4.1 2 4.60-4.80 1 5.45-5.50 1 7.20-7.90 11 H).
Using the procedures indicated, the compounds shown in Table C-1 were prepared.
Table C-i Example Compound Starting Material 1 Starting Material 2 General MS No. 8C-1 3,4- 3-(L-alaninyl)amino-2,3- C-A 498.8 Methylened ioxyphenylacetyl)-L- Methylened joxypheny lacetic dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1- acid 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Aldrich) (Example 8-B3) benzod iazepin-2-one 8C-2 3-(N '-(2-Methoxyphenoxyacetyl)- 2-Methoxyphenoxyacetic 3-(L-alaninyl)amino-2 C-A 500.8 L-alaninyl)amino-2 ,3-dihydro- 1- acid dihydro- 1-methyl-5-phenyl- 1Hmethyl-5-phenyl-l1H- 1,4- (Lancaster) 1 ,4-benzodiazepin-2-one benzod iazepin-2-one 8-B) 8C-3 4-Isopropylphenoxyacetic 3-(L-alaninyl)amino-2, 3- C-A 513.0 Isopropylphenoxyacetyl)-L- acid d ihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1 (Lancaster) 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1 H-I1,4- (Example 8-B) benzodiazepin-2-one 8C-4 3-(N '-(Ethoxyacetyl)-L- Ethoxyacetic acid 3-(L-alaninyl)amino-2 C-A 422.6 alaninyl)amino-2 ,3-dihydro- 1 (Aldrich) dihydro- 1 -methyl-5-phenyl- 1 Hmethyl-5-phenyl-1IH- 1,4- 1 ,4-benzodiazepin-2-one benzodiazepin-2-one Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 3('-(4-Phenoxyphenylacetyl)- 4-Phenoxyphenylacetic acid 3 -(L-alaninyl)amino-2 C-A 547.0 L-alaninyl)amino-2 ,3-dihydro- 1- (Trans World) d ihydro-l1-methyl-5-phenyl- 1Hmethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one iazepin-2-one 8-B) 8C-6 3('-(4-Ethoxyplienylacetyl)-L- 4-Ethoxyphenylacetic acid 3-(L-alaninyl)amino-2 C-A 501.1 alaninyl)amino-2 ,3-dihydro-1 (Aldrich) dihydro-l1-methyl-5-phenyl- 1Hmethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8C-7 2,5 -D imethoxyphenyl acetic 3-(L-alaninyl)amino-2,3- C-A 514.8 Dimethoxyphenylacetyl)-L- acid dihydro-i1-methyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1- (Aldrich) 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 (Example 8-B3) benzod iazepin-2-one 8C-8 3-(N ,5-Difluorobenzoyl)-L- 3, 5-Difluorobenzoic acid 3-(L-alaninyl)amino-2, 3- C-A 1476.8 alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-phenyl- 1Hmethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one _______benzodiazepin-2-one 8-B) 8C-9 3-(N '-(o-Tolylacetyl)-L- o-Tolylacetic acid 3-(L-alaninyl)amino-2 C-A 470.0 alaninyl)amino-2,3-dihydro-1 (Aldrich) dihydro-l1-methyl-5-phenyl- 1Hmethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one Example Compound Starting Material 1 Starting Material 2 General MS No. 8C- 10 3-Diphenylpropionyl)- 3, 3-Diphenylpropionic acid 3-(L-alaninyl)amino-2 C-A 545.0 L-alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro- 1-methyl-S -phenyl- IHmethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one benzod iazepin-2-one 8-B) 8C- 11 3-(N '-(3-Phenoxypropionyl)-L- 3-Phenoxypropionic acid 3 -(L-alaninyl)amino-2 C-A 485.0 alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro- 1-methyl-5-phenyl- 1Hmethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one 8C- 12 3-(N '-(Indole-3-acetyl)-L- Indole-3 -acetic acid 3-(L-alaninyl)amino-2 C-A 494.0 alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-phenyl- 1Hmethyl-5-phenyl-1H-1 I ,4-benzodiazepin-2-one benzod iazepin-2-one 8-B) 8C- 13 4- 3-(L-alaninyl)amino-2,3- C-A 523.0 (Trifluoromethyl)phenylacetyl)- (Trifluoromethyl)phenylacet dihydro-l1-methyl-5-phenyl- IH- L-alaninyl)amino-2 ,3-dihydro- 1- ic acid 1 ,4-benzodiazepin-2-one 1 HI- 1,4- (Maybridge) (Example 8-B) benzodiazepin-2-one_____________ 8C- 14 3-(N '-((4-Methylphenoxy)acetyl)- (4-Methylphenoxy)acetic 3-(L-alaninyl)amino-2 C-A 485.0 L-alaninyl)amino-2 ,3-dihydro- 1- acid dihydro-lI-methyi-5-phenyl- 1Hmethyl-5-phenyl-1H-1 (Aldrich) 1 ,4-benzodiazepin-2-one benzodiazepin-2-one 8-B) Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-1 6 3-(N 4- 3-(L-alaninyl)amino-2 C-A 500.8 (Hydroxymethyl)phenoxyacetyl)- (Hydroxymethyl)phenoxyac dihydro-l1-methyl-5-phenyl- 1H- L-alaninyl)amino-2 ,3-dihydro- 1- etic acid 1 ,4-benzodiazepin-2-one methyl-5-phenyi-l-H-1,4- (Sigm-a) (Example 8-B3) benzod iazepin-2-one 8C- 17 3('-(2-Phenoxyphenylacetyl)- 2-Phenoxyphenylacetic acid 3 -(L-alaninyl)amino-2 C-A 546.8 L-alaninyl)amino-2 ,3-dihydro- 1 (Trans World) dihydro-i1-methyl-5-phenyl- 1Hmethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one 8-B3) 8C- 18 -(3-Phenoxyphenylacetyl)- 3-Phenoxyphenylacetic acid 3-(L-alaninyl)amino-2 C-A 547.0 L-alaninyl)amino-2 ,3 -dihydro- 1- (Aldrich) dihydro-l1-methyl-5-phenyl- 1Hmethyl-5-phenyl-1 H-i1,4- 1 ,4-benzodiazep in-2 -one benzodiazepin-2-one (Example 8-B3) 8C- 19 3-(N 3 ,4-dichlorophenoxyacetic 3-(L-alaninyl)amino-2, 3- C-A 539.2 dichlorophenoxyacetyl)-L- acid dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1- (Aldrich) 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 (Example 8-B3) _________benzodiazepin-2-one 8C-20 -(4-Fluorophenoxyacetyl)- 4-Fluorophenoxyacetic acid 3-(L-alaninyl)amino-2 C-A 489.0 L-alaninyl)amino-2, 3-dihydro- 1- (Aldrich) d ihydro-l1-methyl-5-phenyl- 1H- 1H- 1,4- 1 ,4-benzodiazepin-2-one benzodiazepin-2-one 8-B3) Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-2 1 3-(N'-(Methiylthio)acetyl)-L- (Methylthio)acetic acid 3-(L-alaninyl)amino-2 C-A 424.8 alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-phenyl-l1Hmethyl-5-phenyl-LH-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B3) 8C-22 3-(N '-(Methoxyacetyl)-L- Methoxyacetic acid 3-(L-alaninyl)amino-2 C-A 409.0 alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-phenyl- 1H- 1H- 1,4- 1 ,4-benzodiazepin-2-one benzodiazepin-2-one 8-B) 8C-23 (S)-3-(N'-(Phenoxyacetyl)-L- Phenoxyacetic acid (S)-3-(L-alaninyl)amino-2,3- C-B 471.0 alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro-lI-methyl-5-phenyl- 1Hmethyl-5-phenyl-1H-1 1, 4-benzod iazepin-2 -one iazepin-2-one' (Example 8-B) 8C-24 ()3N'-(Phenylacety Phenylacetic acid (S)-3-(L-alaninyl)amino-2 C-B 455.0 alaninyl)amino-2,3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-phenyl- 1Hmethyl-5-phenyl-1 H- 1,4- 1 ,4-benzodiazepin-2 -one iazepin-2-one (Example 8C-25 ()3N'-(2-Phenoxybutyryl)-L- 2-Phenoxybutyric acid (S)-3-(L-alaninyl)amino-2 C-B 498.8 alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-phenyl- 1Hmethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one _______benzodiazepin-2-one Example Compound Starting Material I Starting Material 2 General MS No. Procedure 8C-26 3-Methoxyphenoxyaceuic (S)-3-(L-alaninyl)amino-2,3- C-B 501.0 Methoxyphenoxyacetyl)-L- acid dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2 3-dihydro- 1- (Aldrich) 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 (Example 8-B3) benzod 8C-28 4-Butoxyphenylacetic acid (S)-3-(L-alaninyl)amino-2 C-B 526.8 Butoxyphenylacetyl)-L- (Lancaster) dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1- 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B3) 8C-29 (S)-3-(L-alaninyl)amino-2 C-B 498.8 Methoxyphenyl)propionyl)-L- Methoxyphenyl)propionic dihydro-l1-methyl-5-phenyl- IHalaninyl)amino-2 ,3-dihydro- 1- acid 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 (Aldrich) (Example 8-B) benzodiazepin-2-one 8C-30 -(4-Fluorophenylacetyl)- 4-Fluorophenylacetic acid (S)-3-(L-alaninyl)amino-2 C-B 472.8 L-alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro-i1-methyl-5-phenyl- IH- 1H- 1,4- 1 ,4-benzodiazepin-2-one iazepin-2-one 8C-3 1 -(Isopropoxylacetyl)-L- Isopropoxylacetic acid (S)-3-(L-alaninyl)amino-2 C-B 436.8 alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-phenyl- 1H- 1H- 1,4- 1 ,4-benzodiazepin-2-one benzodiazepin-2-one 8-B) Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-32 -Phenyl- 1H-tetrazole- 1 -Phenyl- 1H-tetrazole-5- (S)-3-(L-alaninyl)amino-2 C-B 523.0 5-acetyl)-L-alaninyl)amino-2 acetic acid dihydro- 1-methyl-5-phenyl- 1Hdihydro-1-methyl-5-phenyl-1H- (Raap, R. Can. J. Chem. 1 ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one 1968, 46(13), 2255-61) (Example 8-B) 8C-33 3-(3 (S)-3-(L-alaninyl)amino-2 C-B 513.2 methylenedioxyphenyl)propionyl methylenedioxyphenyl) dihydro-l1-methyl-5-phenyl- 1H- )-L-alaninyl)amino-2 ,3-dihydro- propionic acid 1 ,4-benzodiazepin-2-one 1 -methyl-5-phenyl- 1H- 1,4- (Apin) (Example 8-B) benzodiazepin-2-one 8C-34 3-Cyclopentyipropionic acid (S)-3-(L-alaninyl)amino-2,3- C-B 461.0 Cyclopentylpropionyl)-L- (Aldrich) dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2,3-dihydro-1 1 ,4-benzodiazepin-2-one 1H-i (Example 8-B) benzod iazepin-2-one 8C-35 '-(2-Cyclopentene- 1- 2-Cyclopentene- 1 -acetic (S)-3-(L-alaninyl)amino-2 C-B 445.0 acetyl)-L-alaninyl)amino-2,3- acid d ihydro- 1 -methyl-5-phenyl- 1 H- 1H- (Aldrich) 1 ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one 8-B) 8C-36 (S)-3-(N'-(2-Chloro-6- 2-Chloro-6- (S)-3-(L-alaninyl)amino-2,3- C-B 507.0 fluorophenylacetyl)-L- fluorophenylacetic acid dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1- (Aldrich) 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1 H-i (Example 8-B) _______benzodiazepin-2-one Example Compound Starting Material 1 Starting Material 2 Genera! MS No. ________Procedure 8C-37 (S)-3-(N'-(Cyclohexylacetyl)-L- Cyclohexylacetic acid -(L-alaninyl)amino-2 C-B 461.0 alaninyl)amino-2, 3-dihydro- 1- (Aldrich) dihydro-i1-methyl-5-phenyl- 1Hmethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B3) 8C-38 2 ,5-Difluorophenylacetic (S)-3-(L-alaninyl)amino-2,3- C-B 491.2 Difluorophenylacetyl)-L- acid dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1- (Aldrich) 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 (Example 8-B3) benzodiazepin-2-one 8C-39 Pentafluorophenoxyacetic -(L-alaninyl)amino-2 C-B 561.0 (Pentafluorophenoxyacetyl)-L- acid dihydro- 1-methyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1- (Aldrich) 1 ,4-benzod iazepin-2 -one methyl-5-phenyl-1H-1 (Example 8-B3) benzodiazepin-2-one 8C-40 3 ,5-Dimethylphenoxyacetic (S)-3-(L-alaninyl)amino-2 C-B 498.8 Dimethylphenoxyacetyl)-L- acid dihydro-lI-methyl-5-pheny 1-1Halaninyl)amino-2 ,3-dihydro- 1- (Sigma-Aldrich Rare 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 Chemicals) (Example 8-B) benzodiazepin-2-one 8C-4 1 '-(4-Chiorophenylacetyl)- 4-Chloropheny lacetic acid (S)-3-(L-alaninyl)amino-2 C-B 489.2 L-alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro- 1-methyl-5-phenyl- 1 LH- 1,4- 1 ,4-benzodiazepin-2 -one benzodiazepin-2-one Example Compound Starting Material 1 Starting Material 2 General MS No. 8C-42 3-Chlorophenoxyacetic acid (S)-3-(L-aianinyl)amino-2 C-B 505.0 Chlorophenoxyacetyl)-L- (Lancaster) dihydro- 1-methyl-5-phenyl-l1Halaninyi)amino-2 ,3-dihydro- 1- 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 (Example 8-B) benzod iazepin-2-one 8C-43 (S)-3-(N'-(Benzo [bi thiophene-3- Benzo thiophene-3- (S)-3-(L-alaninyl)amino-2,3- C-B 511.2 acetyl)-L-alaninyl)amino-2 acetic acid dihydro- 1-methyl-5-phenyl-l1Hdihydro- 1-methyl-5-phenyl- 1H- (Lancaster) 1 ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one 8-B) 8C-44 '-(Benzoylformnyl)-L- Benzoylformic acid (S)-3-(L-alaninyl)amino-2 C-B 468.8 alaninyl)amino-2, 3-dihydro- 1- (Aldrich) dihydro- 1-methyl-5-phenyl- 1Hmethyl-5-phenyl-IH-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one 8C-45 3, 5-Dimethoxyphenylacetic (S)-3-(L-alaninyl)amnino-2 C-B 515.0 Dimethoxyphenylacetyl)-L- acid dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2 ,3 -dihydro- 1- (Aldrich) 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 (Example 8-B) benzodiazepin-2-one 8C-46 2, 5-Dimethylphenylacetic -(L-alaninyl)amino-2,3- C-B 483.2 Dimethylphenylacetyl)-L- acid dihydro- 1-methyl-S -phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1- (Lancaster) 1 ,4-benzodiazepin-2-one methyl-5-phenyl-l1H- 1,4- (Example 8-B) __benzodiazepin-2-one I Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-47 2 ,6-Difluorophenylacetic (S)-3-(L-alaninyl)amino-2 C-B 491.2 Difluorophenylacetyl)-L- acid dihydro-l1-methyl-5-phenyl-l1Halaninyl)amino-2 ,3-dihydro- 1- (Aldrich) 1 ,4-benzodiazepin-2-one 1H- 1,4- (Example 8-B3) benzod 8C-48 2 ,4-Difluorophenylacetic (S)-3-(L-alaninyl)amino-2 C-B 491.0 Difluorophenylacetyl)-L- acid dihydro-i1-methyl-5-phenyl-l1Halaninyl)amino-2 ,3-dihydro- 1- (Aldrich) 1 ,4-benzodiazepin-2-one methyl-5-phenyl-lH-1 (Example 8-B) benzodiazepin-2-one 8C-49 -(Mesitylacetyl)-L- Mesitylacetic acid (S)-3-(L-alaninyl)amino-2 C-B 497.0 alaninyl)amino-2 ,3-diliydro- 1- (Lancaster) dihydro-i1-methyl-5-phenyl-l1Hmethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one 8-B) 8C-50 (S)-3-(N'-(4-Biphenylacetyl)-L- 4-Biphenylacetic: acid (S)-3-(L-alaninyl)amino-2,3- C-B 531.2 alaninyl)amino-2 ,3-dihydro- 1 (Lancaster) dihydro- 1-methyl-5-phenyl- 1Hmethyl-5-phienyl-1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-51 3,4-Difluorophenylacetic (S)-3-(L-alaninyl)amino-2,3- C-B 491.2 Difluorophenylacetyl)-L- acid dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1- (Aldrich) 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 (Example 8-B) benzodiazepin-2-one Example Compound Starting Material 1 Starting Material 2 General MIS No. Procedure 8C-52 (S)-3-(N'-(trans-Styrylacetyl)-L- trans-Styrylacetic acid (S)-3-(L-alaninyl)amino-2,3-- C-B 481.2 alaninyl)amino-2 3-d ihydro- 1- (Aldrich) dihydro-l1-methy 1-5-phenyl- 1Hmethyl-5-phenyi-1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one 8-B) 8C-53 -(3-Benzoylpropionyl)- 3-Benzoy Ipropionic acid -(L-alaninyl)amino-2 C-B 497.0 L-alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro- 1-methyl-5-phenyl- 1Hmethyl-5-phenyl-1H-1,4- 1 ,4-benzodiazepin-2-one _______benzodiazepin-2-one 8-B) 8C-54 -(trans-3-Hexenoyl)-L- trans-3-Hexenoic acid (S)-3-(L-alaninyl)amino-2 C-B 433.2 alaninyl)amino-2, 3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-phenyl- 1H- 1H- 1,4- 1 ,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-55 -(Heptanoyl)-L- Heptanoic acid -(L-alaninyl)amino-2 C-B 449.0 alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-phenyl- 11methyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-56 (S)-3-(L-alaninyl)amino-2,3- C-B 483.2 Methylphenyl)propionyl)-L- Methylphenyl)propionic dihydro-l1-methyl-S-phenyl-l1Halaninyl)amino-2 ,3-dihydro- 1 acid 1 ,4-benzodiazepin-2-one 1H- 1,4- (Lancaster) (Example 8-B) __benzodiazepiri-2-one I_ I_ _I_ Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-57 (S)-3-(L-alaninyl)amino-2,3- C-B 503.0 Chlorophenyl)propionyl)-L- Chlorophenyl)propionic dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1- acid 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Trans World) (Example 8-B3) benzodiazepin-2-one 8C-58 -Phenylbutyryl)-L- 3-Phenylbutyric acid -(L-alaninyl)amino-2 C-B 483.2 alaninyl)amino-2,3-dihydro- 1- (Aldrich) dihydro-i1-methyl-5-phenyl- 1H- 1H- 1,4- 1 ,4-benzodiazepin-2 -one benzodiazepin-2-one 8-B) 8C-59 4-(4-Methoxyphenyl)butyric (S)-3-(L-alaninyl)amino-2, 3- C-B 513.2 Methoxyphenyl)butyryl)-L- acid dihydro- 1 -methyl-5*-phenyl- 1 Halaninyl)amino-2 ,3-d ihydro- 1 (Aldrich) I ,4-benzod iazepin-2-one 1,4- (Example 8-B3) benzodiazepin-2-one 8C-60 mono-Methyl succinate (S)-3-(L-alaninyl)amino-2,3- C-B 1451.0 Methoxycarbonylpropionyl)-L- dihydro- 1-inethyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1- Methoxycarbonylpropionic 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- acid) (Example 8-B) benzodiazepin-2-one (Aldrich) 8C-6 1 ()3N'-(4-Phenylbutyryl)-L- 4-Phenylbutyric acid (S)-3-(L-alaninyl)amino-2 C-B 483.2 alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-phenyl- 1H- 1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one Example Compound Starting Material 1 Starting Material 2 General MS No. 8C-62 3 -(Benzyl thio)prop ionic (S)-3-(L-alaninyl)amino-2 C-B 515.2 (Benzylthio)propionyl)-L- acid dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1- (Sigma-Aldrich Rare 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- Chemicals) (Example 8-B) benzodiazepin-2-one__ 8C-63 '-(3-Methylpentanoyl)-L- 3-Methylpentanoic acid (S)-3-(L-alaninyl)amino-2 C-B 435.2 alaninyl)amino-2 ,3-dihydro-1 (Aldrich) dihydro-l1-methyl-5-phenyl- 1Hmethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-64 Suberic acid monomethyl (S)-3-(L-alaninyl)amino-2,3- C-B 507.0 Methoxycarbonylheptanoyl)-L- ester(6- dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1 Methoxycarbonylheptanoic 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 acid) (Example 8-B) 8C-65 -(2-lndanylacetyl)-L- 2-Indanylacetic acid (S)-3-(L-alaninyl)amino-2 C-B 495.0 alaninyl)amino-2 ,3-dihydro- 1 (Lancaster) dihydro- 1 -methyl-5-phenyl- 1 Hmethyl-5-phenyl-1 H- 1,4- 1 ,4-benzodiazepin-2-one _______benzodiazepin-2-one 8-B) 8C-66 4-Methoxyphenylacetic acid -(L-alIan inylI)amino-2,3- C-C 485.2 Methoxyphenylacetyl)-L- (Aldrich) dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2,3-dihydro- 1- 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 (Example 8-B) benzodiazepin-2-one Example Compound Starting Material I Starting Material 2 General MS No. _________Procedure 8C-67 o-Chlorophenoxyacetic acid (S)-3-(L-alaninyl)amino-2 C-C 505.0 Chlorophenoxyacetyl)-L- (Lancaster) dihydro-l1-methyl-S -phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1- 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 (Example 8-B3) benzodiazepin-2-one 8C-68 '-(2-Thiopheneacetyl)-L- 2-Thiopheneacetic acid (S)-3-(L-alaninyl)amino-2,3- C-C 461.0 alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-phenyl- 1Hmethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one benzod iazepin-2-one 8-B3) 8C-69 3- (S)-3-(L-alaninyl)amino-2,3- C-C 523.0 (Trifluoromethyl)phenylacetyl)- (Trifluoromethyl)phenylacet dihydro-l1-methyl-5-phenyl- 1H- L-alaninyl)amino-2 ,3-dihydro- 1- ic acid 1 ,4-benzodiazepin-2-one 1H- 1,4- (Marshallton) (Example 8-B3) benzodiazepin-2-one 8C-70 -(p-Tolylacetyl)-L- p-Toly lacetic acid -(L-alaninyl)amino-2, 3- C-C 469.0 alaninyl)amino-2,3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-phenyl- 1Hmethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-7 1 2 ,6-Difluoromandelic acid (S)-3-(L-alaninyl)amnino-2,3- C-D 448.0 Difluoromandelyl)-L- (Fluorochem) dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2,3-dihydro-1 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H- 1,4- (Example 8-B) benzodiazepin-2-one Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-72 3(4- (S)-3-(L-alaninyl)amino-2 c-C 499.0 Methoxyphenyl)propionyl)-L- Methoxyphenyl)prop ionic dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1- acid 1 ,4-benzodiazepin-2-one IH- 1,4- (Aldrich) (Example 8-B) benzodiazepin-2-one 8C-73 3 ,5-Difluorophenylacetic (S)-3-(L-alaninyl)amino-2 C-C 491.0 Difluorophenylacetyl)-L- acid dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1- (Aldrich) 1 ,4-benzodiazepin-2-one 1H- 1,4- (Example 8-B) ________benzodiazepin-2-one 8C-74 -(m-Tolylacetyl)-L- m-Tolylacetic acid (S)-3-(L-alaninyl)amino-2 C-C 469.0 alaninyl)amino-2,3-d ihydro- 1- (Aldrich) dihydro-l1-methyl-5-phenyl- 1Hmethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one 8-B) 8C-75 -(3-Fluorophenylacetyl)- 3-Fluorophenylacetic acid (S)-3-(L-alaninyl)amino-2 C-C 473.0 L-alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro- 1-methyl-5-phenyl- 1Hmethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one 8C-76 4-Chiorophenoxyacetic acid (S)-3-(L-alaninyl)amino-2,3- C-C 1505.0 Chlorophenoxyacetyl)-L- (Grand Island Biological dihydro- 1-methyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1 Company) 1 ,4-benzodiazepin-2 -one methyl-5-phenyl-1H-1 (Example 8-B) enzodiazepin-2-one_____________ Example Compound Starting Material 1 Starting Material 2 General MIS No. Procedure 8C-77 '-(2-Naphithylacetyl)-L- 2-Naphthylacetic acid (S)-3-(L-alaninyl)amino-2 C-C 505.2 alaninyl)amino-2, 3-dihydro- 1- (Aldrich) dihydro- I-methyl-5-phenyl- IHmetliyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-78 (S)-3-(N'-(3-Chloropheny lacetyl)- 3-Chiorophenylacetic acid (S)-3-(L-alaninyl)amino-2 C-C 489.2 L-alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-phenyl- 1Hmethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B3) 8C-79 3-Methylphenoxyacetic acid (S)-3-(L-alaninyl)amino-2 C-C 485.2 Methylphenoxyacetyl)-L- (Lancaster) dihydro-l1-methyl-5-phenyl- 11alaninyl)amino-2,3-dihydro- 1- 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B3) benzodiazepin-2-one 8C-80 3,4- (S)-3-(L-alaninyl)amino-2 C-C 499.0 Methylenedioxyphenylacetyl)-L- Methylenedioxyphenylacetic dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1- acid 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 (Aldrich) (Example 8-B) benzod 8C-8 1 2-Methoxyphenoxyacetic (S)-3-(L-alaninyl)amino-2 c-c 501.0 Methoxyphenoxyacetyl)-L- acid dihydro- I-methyl-5-phenyl- 111alaninyl)amino-2 ,3-dihydro- 1- (Lancaster) 1 ,4-benzodiazepin-2-one methyl-5-phenyl-l1H-i A- (Example 8-B3) _______benzodiazepin-2-one Example Compound Starting Material 1 Starting Material 2 General MS No. 8C-82 4-Isopropylphenoxyacetic (S)-3-(L-alaniny I)amino-2 C-C 513.2 Isopropylphenoxyacetyl)-L- acid dihydro- 1-methyl-5-phenyl- 1Halaninyl)amino-2 3-dihydro- 1- (Lancaster) 1 ,4-benzodiazepin-2-one methyl-5-phenyl-IH-1,A- (Example 8-B) 8C-83 4-Phenoxyphenylacetic acid (S)-3-(L-alaninyl)amino-2 C-C 547.0 Phenoxyphenylacetyl)-L- (Trans World) dihydro- 1-methyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1- 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 (Example.8-B) benzodiazepin-2-one 8C-84 Phenylmercaptoacetic acid (S)-3-(L-alaninyl)amino-2,3- C-C 487.2 (Pheny lmercaptoacetyl)-L- (Aldrich) dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1- 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 (Example 8-B3) 8C-85 4-Ethoxyphenylacetic acid (S)-3-(L-alaninyl)amino-2 C-C 499.0 Ethoxyphenylacetyl)-L- (Aldrich) dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2,3-dihydro-1 1 ,4-benzodiazepin-2-one methyl-5-phenyl-l1H- 1,4- (Example 8-B3) benzodiazepin-2-one_____________ Example Compound Starting Material 1 Starting Material 2 General MS No. 8C-86 2,5 -Dimethoxyphenyl]acetic (S)-3-(L-alaninyl)amino-2 C-C 515.0 Dimethoxyphenylacetyl)-L- acid dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1- (Aldrich) 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 (Example 8-B) benzodiazepin-2-one 8C-87 '-(o-Tolylacetyl)-L- o-Tolylacetic acid (S)-3-(L-alaninyl)amino-2 C-C 469.0 alaninyl)amino-2 ,3-d ihydro-1 (Aldrich) dihydro-l1-methyl-5-phenyl- 1Hmethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-88 3, 3-Diphenylpropionic acid (S)-3-(L-alaninyl)amino-2 C-C 545.3 Diphenylpropionyl)-L- (Aldrich) dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2,3-dihydro-1 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 (Example 8-B) benzodiazepin-2-one 8C-89 '-(3-Phenoxypropionyl)- 3-Phenoxypropionic acid (S)-3-(L-alaninyl)aniino-2 C-C 485.4 L-alaninyl)amino-2,3-dihydro- 1- (Aldrich) d ihydro-l1-methyl-5-phenyl- 1H- 1H- 1,4- 1 ,4-benzodiazepin-2-one benzodiazepin-2-one 8-B) 8C-90 -(Indole-3 -acetyl)-L- Indole-3-acetic acid (S)-3-(L-alaninyl)amino-2 C-C 494.0 alaninyl)amino-2 ,3-d ihydro- 1- (Aldrich) dihydro-l1-methyl-5-phenyl- 1H- IH- 1,4- 1 ,4-benzodiazepin-2-one benzodiazepin-2-one Example Compound Starting Material 1 Starting Material 2 General MIS No. 8C-91 4- (S)-3-(L-alaninyl)amino-2,3- C-C 523.0 (Trifluoromethyl)phenylacetyl)- (Trifluoromethyl)phenylacet dihydro- 1-methyl-5-phenyl-l1H- L-alaninyl)amino-2 ,3-dihydro- 1- ic acid 1 ,4-benzodiazepin-2-one 1H- 1,4- (Maybridge) (Example 8-B) benzodiazepin-2-one 8C-92 3,5- (S)-3-(L-alaninyl)amino-2,3- C-C 591.0 Bis(trifluoromethyl)phenylacetyl Bis(trifluoromethyl)phenyla dihydro-l1-methyl-5-phenyl- 1H- )-L-alaninyl)amino-2 ,3-dihydro- cetic acid 1 ,4-benzodiazepin-2-one 1 -methyl-5-phenyl-l1H- 1,4- (Aldrich) (Example 8-B) benzodiazepin-2-one 8C-93 2-Phenoxyphenylacetic acid (S)-3-(L-alaninyl)amino-2 C-C 547.0 Phenoxyphenylacetyl)-L- (Trans World) dihydro-l1-methyl-5-phenyl-l1Halaninyl)amino-2,3-dihydro- 1- 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 (Example 8-B) benzodiazepin-2-one 8C-94 3-Phenoxyphenylacetic acid (S)-3-(L-alaninyl)amino-2 C-D 547.0 Phenoxyphenylacetyl)-L- (Aldrich) dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2,3-dihydro- 1- 1 ,4-benzodiazepin-2-one 1,4- (Example 8-B) I benzodiazepin-2-one Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-95 4-Fluorophenoxyacetic acid (S)-3-(L-alaninyl)amino-2 C-c 489.2 Fluorophenoxyacetyl)-L- (Aldrich) dihydro-l1-methyl-5-phenyl- lHalaninyl)amino-2 ,3-dihydro-1 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 (Example 8-B3) benzodiazepin-2-one 8C-96 2,4-Dichlorophenylacetic (S)-3-(L-alaninyl)amino-2 C-C 52 Dichlorophenylacetyl)-L- acid dihydro-l1-methyl-5-phenyl-1 Halaninyl)amino-2 ,3-dihydro- 1- (Fairfield) 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 (Example 8-B) benzodiazepin-2-one 8C-97 '-((Methylthio)acetyl)-L- (Methylthio)acetic acid (S)-3-(L-alaninyl)amino-2 C-C 425.0 alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro- i-methyl-5-phenyl- 1Hmethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8C-98 -(4-Fluoromandelyl)-L- 4-Fluoromandelic acid (S)-3-(L-alaninyl)amino-2 C-D 489.0 alaninyl)amino-2 ,3-d ihydro- 1- (Lancaster) dihydro- 1-methyl-5-phenyl- 1Hmethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-99 4-Thionaphthenacetic acid (S)-3-(L-alaninyl)amino-2,3- C-C '511.2 Thionaphthenacetyl)-L- (Aldrich) dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1- 1 ,4-benzodiazepin-2-one IH- 1,4- (Example 8-B) Example Compound Starting Material 1 Starting Material 2 General MIS No. 8C- 100 '-(Methoxyacetyl)-L- Methoxyacetic acid -(L-alaninyl)amino-2 C-C 409.0 alaninyl)amino-2, 3-dihydro- 1- (Aldrich) dihydro- 1-methyl-S -phenyl- IH- 1H- 1,4- 1 ,4-benzodiazepin-2-one benzod iazepin-2-one (Example 8-B3) 8C- 101 -(Ethoxyacetyl)-L- Ethoxyacetic acid -(L-alaninyl)amino-2 C-C 422.8 alaninyl)amino-2 ,3-dihydro- 1 (Aldrich) dihydro-l1-methyl-5-phenyl- 1Hmethyl-5-phenyl-l1H- 1,4- 1 ,4-benzodiazepin-2-one _______benzodiazepin-2-one (Example 8-B3) 8C- 102 -(3-Indolepropionyl)-L- 3-Indolepropionic acid (S)-3-(L-alaninyl)amino-2 C-C 508.2 alaninyl)amino-2 ,3-dihydro- 1 (Aldrich) dihydro- 1 -methyl-5-phenyl- 1 Hmethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one benzod iazepin-2-one 8-B3) 8C- 103 (S)-3-(L-alaninyl)amino-2 C-C 503.0 Chlorophenyl)propionyl)-L- Chlorophenyl)propionic dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1- acid 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 (Trans World) (Example 8-B) benzodiazepin-2-one_____________ 8C- 104 -(Butyryl)-L- Butyric acid (S)-3-(L-alaninyl)amino-2 C-C 407.2 alaninyl)amino-2,3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-phenyl- 1Hmethyl-5-phenyl-IH-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one 8-B3) Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-105 (S)-3-(N'-(Hexanoyl)-L- Hexanoic acid (S)-3-(L-alaninyl)amino-2,3- c-C 435.0 alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-phenyl- 1Hmethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C- 106 -(5-Phenylpentanoyl)-L- 5-Phenylvaleric acid (S)-3-(L-alaninyl)amino,-2 c-C 497.0 alaninyl)amino-2, 3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-phenyl-l1Hmethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one 8-B3) 8C- 107 -(4-(2-Thienyl)butyryl)- 4-(2-Thienyl)butyric acid (S)-3-(L-alaninyl)amino,-2 C-C 489.2 L-alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-phenyl- 1H- 1H- 1,4- 1 ,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8C- 108 4-Nitrophenoxyacetic acid (S)-3-(L-alaninyl)amnino,-2 C-C 516.2 Nitrophenoxyacetyl)-L- (Apin) dihydro-l1-methyl-5-phenyl-l1Halaninyl)amino-2,3-dihydro-1 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 (Example 8-B) benzodiazepin-2-one_______________ 8C- 109 (S)-3-(L-alaninyl)amino-2 C-C 499.0 Methoxyphenyl)propionyl)-L- Methoxyphenyl)propionic dihydro- 1-methyl-5-phenyl- 1Halaninyl)amino-2 dihydro- 1- acid 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 (Lancaster) (Example 8-B) benzodiazepin-2-one 1_ Example Compound Starting Material 1 Starting Material 2 General MS ]NO. Procedure 8C- 110 '-(5-Methylhexanoyl)-L- 5-Methyihexanoic acid (S)-3-(L-alaninyl)amino-2 C-C 449.0 alaninyl)amino-2 ,3-dihydro- 1- (Pfalz and Bauer) dihydro- 1-methyl-5-phenyl- IH- 1H- 1,4- 1 ,4-benzodiazepin-2-one benzodiazepin-2-one 8-B) 8C-1 11 Hydrocinnamyl)-L- Hydrocinnamic acid (S)-3-(L-alaninyl)amino-2,3- C-C 469.0 alaninyl)amino-2,3-dihydro-1 (Aldrich) dihydro-1 -methyl-5-phenyl-1 Hmethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one iazepin-2-one 8-B) 8C- 112 (S)-3-(N'-(Octanoyl)-L- Octanoic acid (S)-3-(L-alaninyl)amino-2,3- C-C 463.2 alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-phenyl- 1Hmethyl-5-phenyl-1 H-i 1 ,4-benzodiazepin-2-one _______benzodiazepin-2-one (Example 8C-113 (S)-3-(L-alaninyl)amino-2,3- C-D 485.2 Hydroxyphenyl)propionyl)-L- Hydroxyphenyl)propionic dihydro-1 -methyl-5 -phenyl-l1Halaninyl)amino-2 ,3-dihydro- 1- acid 1 ,4-benzodiazepin-2-one 1H- 1,4- (Lancaster) (Example 8-B) benzodiazepin-2-one 8C- 114 (S)-3-(L-aianinyl)amino-2,3- C-D 485.2 Hydroxyphenyl)propionyl)-L- Hydroxyphenyl)propionic dihydro- I-methyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1- .acid 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 (Aldrich) (Example 8-B) benzodiazepin-2-one
I_
Example Compound Starting Material I Starting Material 2 General MS No. Procedure 8C- 115 3 ,4,5-Trifluorophenylacetic (S)-3-(L-alaninyl)amino-2,3- C-C 509.0 Trifluorophenylacetyl)-L- acid dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1- (Fluorochem) 1 ,4-benzodiazepin-2-one 1H- 1,4- (Example 8-B) benzodiazepin-2-one 8C- 116 '-(5-Hydantoinacetyl)-L- 5-Hydantoinacetic acid (S)-3-(L-alaninyl)amino-2 C-C 477.0 alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-phenyl- 1H- 1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one 8-B) 8C- 117 (S)-3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic acid (S)-3-(L-alaninyl)amino-2 C-C 447.0 alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-phenyl- 1Hmethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C- 118 3-(Trifluoromethyl)butyric (S)-3-(L-alaninyl)amino-2 C-C 475.0 (Trifluoromethyl)butyryl)-L- acid dihydro-l1-methyl-5-phenyl- 1Halaninyl)arnino-2 ,3-dihydro- 1- (Fluorochem) 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 .(Example 8-B) benzodiazepin-2-one________________ 8C-1 19 (S)-3-(N'-(2-Methyl-3- 2-Methyl-3- (S)-3-(L-alaninyl)amino-2,3- C-C 509.2 Benzofuranacetyl)-L- Benzofuranacetic acid dihydro-l1-methyl-5-phenyl-l1Halaninyl)amino-2 ,3-dihydro- 1- (Maybridge) 1 ,4-benzodiazepin-2-one 1H-1 (Example 8-B) __benzodiazepin-2-one I_ I I_ I_ I Example Compound Starting Material 1 Starting Material 2 General MS No. 8C- 120 ()3N'-(Propionyl)-L- Propionic acid (S)-3-(L-alaninyl)amino-2 C-C 393.0 alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-phenyl- 1Hmethyl-5-phenyl-IH-1 1, 4-benzod iazepin-2 -one benzodiazepin-2-one 8-B3) 8C- 121 '-(Cyclopropylacety Cyclopropylacetic acid (S)-3-(L-alaninyl)amino-2 C-C 419.0 alaninyl)amino-2 ,3-dihydro- 1- (Lancaster) dihydro- 1-methyl-5-phenyl- IHmethyl-5-phenyl-1H-1 I ,4-benzod iazep in-2 -one benzodiazepin-2-one (Example 8-B) 8C- 122 -(3-Methoxypropionyl)- 3-Methoxypropionic acid (S)-3-(L-alaninyl)amino-2 C-C 423.2 L-alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-phenyl- 1Hmethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one 8C- 123 '-(5-(Thienyl)pentanoyl)- 5-(Thienyl)pentanoic acid (S)-3-(L-alaninyl)amino-2 C-C 503.0 L-alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-phenyl- 1Hmethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one benzod iazepin-2-one (Example 8-B) 8C- 124 -(L-alaninyl)amino-2 C-C 487.2 Fluorophenyl)propionyl)-L- Fluorophenyl)propionic acid dihydro- 1-methyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1- (Trans World) 1 ,4-benzodiazepin-2-one methyl-i -phenyl-1H-1 (Example 8-B3) _______benzodiazepin-2-one Example Compound Starting Material 1 Starting Material 2 General MIS No. Procedure 8C-125 (S)-3-(L-alaninyl)amino-2,3- c-C 503.0 Fluorophenoxy)propionyl)-L- Fluorophenoxy)propionic dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1- acid 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 (Maybridge) (Example 8-B) benzodiazepin-2-one_____________ 8C-126 (S)-3-(N'-(2-Norbornaneacetyl)- 2-Norbornaneacetic acid (S)-3-(L-alaninyl)amino-2,3- C-C 473.0 L-alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro- 1-methyl-5-phenyl-l1H- 1,4- 1 ,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8C- 128 2, 3-Difluoromandelic acid (S)-3-(L-alaninyl)amino-2 C-C 507.0 Difluoromandelyl)-L- (Fluorochem) dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2,3-dihydro- 1- 1 ,4-benzodiazepin-2-one 1H- 1,4- (Example 8-B) benzodiazepin-2-one 8C- 129 -(3-Pentenoyl)-L- 3-Pentenoic acid (S)-3-(L-alaninyl)amino-2 C-C 419.0 alaninyl)amino-2 ,3-d ihydro- 1- (Fluka) dihydro-l1-methyl-5-phenyl- IH- 1H- 1,4- 1 ,4-benzodiazepin-2-one benzodiazepin-2-one 8C- 130 (S)-3-(L-alaninyl)amino-2,3- C-C 567.2 dichlorophenoxy)butyryl)-L- dichlorophenoxy)butyric dihydro- 1-methyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1- acid 1 ,4-benzodiazepin-2-one 1H- 1,4- (Aldrich) (Example 8-B) ______benzodiazepin-2-one Example Compound Starting Material 1 Starting Material 2 General MS No. 8C- 131 2 ,3-Dichlorophenoxyacetic (S)-3-(L-alaninyl)aminb-2 C-C 539.2 Dichlorophenoxyacetyl)-L- acid dihydro-l1-methyl-5-phenyl-l1Halaninyl)amino-2 ,3-dihydro- 1- (Aldrich) 1 ,4-benzodiazepin-2-one metliyl-5-phenyl-IH-1 (Example 8-B3) benzodiazepin-2-one 8C- 133 '-(2-Fluorophenylacetyl)- 2-Fluorophenylacetic acid (S)-3-(L-alaninyl)amino-2 C-C 473.0 L-alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-phenyl- 1H- 1H- 1,4- 1 ,4-benzodiazepin-2-one benzodiazepin-2-one 8-B) 8C-135 '-(2-Nitrophenylacetyl)- 2-Nitrophenylacetic acid (S)-3-(L-alaninyl)amino-2,3- C-C 499.8 L-alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro- 1-methyl-5-phenyl- 1Hmethyl-5-phenyl-IH-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B3) 8C-136 4- (S)-3-(L-alaninyl)amino-2,3- C-C 501.0 (Hydroxymethyl)phenoxyacetyl)- (Hydroxymethyl)phenoxyac dihydro-l1-methyl-5-phenyl-1 H- L-alaninyl)amino-2 ,3-dihydro- 1- etic acid 1 ,4-benzodiazepin-2-one 1H- 1,4- (Sigma) (Example 8-B) benzod iazepin-2-one 8C-137 (S)-3-(N'-(2-Fluoro-3- 2-Fluoro-3- (S)-3-(L-alatninyl)amino-2,3- C-C 541.0 (trifluoromethyl)phenylacetyl)-L- (trifluoromethyl)phenylaceti dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2,3-dihydro-1- c acid 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 (Fluorochem) (Example 8-B) _________benzodiazepin-2-one__ Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C- 138 2,4 ,6-Trifluorophenylacetic (S)-3-(L-alaninyl)amino-2,3- C-C 509.0 Trifluorophenylacetyl)-L- .acid dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1- (Fluorochem) 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 (Example 8-B3) benzodiazepin-2-one 8C- 139 '-(4-Fluoro-2- 4-Fluoro-2- (S)-3-(L-aianinyl)amino,-2 C-C 541.0 (trifluoromethyi)phenylacetyl)-L- (trifluoromethyl)phenylaceti dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2,3-dihydro-1- c acid 1 ,4-benzodiazepin-2-one 1H- 1,4- (Fluorochem) (Example 8-B3) benzodiazepin-2-one 8C- 140 4,4 ,4-Trifluorobutyric acid (S)-3-(L-alaninyl)amino-2 C-C 461.0 Trifluorobutyryl)-L- (Fluorochem) dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1- 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 (Example 8-B) benzodiazepin-2-one 8C- 141* -(2-Fluoro-4- 2-Fluoro-4- (S)-3-(L-alaninyl)amino-2 C-C 541.0 (trifluoromethyl)phenylacetyl)-L- (trifluoromethyl)phenylaceti dihydro- 1 methyl-5-phenyl- 111alaninyl)amino-2 ,3-dihydro- 1- c acid 1 ,4-benzodiazepin-2-one methyl-5-phenyl-l1H- 1,4- (Fluorochem) (Example 8-B3) benzodiazepin-2-one 8C- 142 -(4-Bromophenylacetyl)- 4-Bromophenylacetic acid (S)-3-(L-alaninyl)amino-2 C-C 533.0 L-alaninyl)amino-2,3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-phenyl- 1Hmethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one (Example Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-143 (S)-3-(L-alaninyl)amino-2,3- C-C 515.0 Fluorobenzoyl)propionyl)-L- Fluorobenzoyl)propionic dihydro-i1-methyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1- acid 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 (Aldrich) (Example 8-B) benzodiazepin-2-one 8C- 144 (2-Methylphenoxy)acetic (S)-3-(L-alaninyl)amino-2 C-C 485.2 Methylphenoxy)acetyl)-L- acid dihydro- 1-methyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1- (Lancaster) 1 ,4-benzodiazepin-2-one 1H- 1,4- (Example 8-B3) benzodiazepin-2-one 8C-145 4-Methoxyphenoxyacetic (S)-3-(L-alaninyl)amino-2,3- C-C 501.0 Methoxyphenoxyacetyl)-L- acid dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2,3-dihydro- 1- (Lancaster) 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 (Example 8-B) benzodiazepin-2-one_______________ 8C- 146 3-(Phenylsulfonyl)propionic (S)-3-(L-alaninyl)amino-2 C-C 531 (Phenylsulfonyl)propionyl)-L- acid dihydro-l1-methyl-5-phenyl- 1H- (M-1) alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 (Example 8-B) __benzodiazepin-2-one I I I_ Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C- 147 2-Metlioxyphenylacetic acid (S)-3-(L-alaninyl)amino-2 C-C 485.2 Methoxyphenylacetyl)-L- (Aldrich) dihydro- 1-methyl-5-phenyl- 1Halaninyl)amino-2,3-dihydro-1 1 ,4-benzodiazepin-2-one methyl-5-phenyl-lH-1 (Example 8-B) benzodiazepin-2-one 8C- 148 (S)-3-(N'-(2-Bromophenylacetyl)- 2-Bromophenylacetic acid (S)-3-(L-alaninyl)amino-2 C-C 535.0 L-alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-phenyl- 1Imethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C- 149 (S)-3-(N'-(p-Isopropyl p-Isopropyl phenylacetic (S)-3-(L-alaninyl)amino-2, 3- C-C 497.0 phenylacetyl)-L-alaninyl)amino- acid dihydro-l1-methyl-5-phenyl- 1H- 2 ,3-dihydro-lI-methyl-5-phenyl- (Lancaster) 1 ,4-benzodiazepin-2-one 1H- 1,4-benzodiazepin-2-one 8-B3) 8C- 150 '-(4-Pentenoyl)-L- 4-Pentenoic acid (S)-3-(L-alaninyl)amino-2 C-C 419.0 alaninyl)amino-2,3-dihydro- 1- (Aldrich) dihydro-1 -methyl-5-phenyl- 1Hmethyi-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one benzod iazepin-2-one 8-B) 8C- 151 4-Hydroxyphenoxyacetic (S--Laaiy~m 3- C-D 487.2 Hydroxyphenoxyacetyl)-L- acid dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1- (Acros) 1 ,4-benzodiazepin-2-one methyl-5-phenyl-l1H- 1,4- (Example 8-B) benzodiazepin-2-one Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-152 (S)-3-(N'-(4-Oxopentanoyl)-L- Levulinic acid (S)-3-(L-alaninyl)amino-2,3- c-C 433.1 alaninyl)amino-2 ,3-dihydro- 1- (4-Oxopentanoic acid) dihydro-l1-methyl-5-phenyl- IH- 1) methyl-5-phenyl-1H-1 (Aldrich) 1 ,4-benzodiazepin-2-one benzod iazepin-2-one (Example 8-B) 8C-153 2-Hydroxyphenylacetic acid (S)-3-(L-alaninyl)amino-2,3- C-D 471.0 Hydroxyphenylacetyl)-L- (Aldrich) dihydro-i1-methyl-5-phenyl-l1Halaninyl)amino-2,3-dihydro- 1- 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 (Example 8-B) 8C- 154 3 ,4-Dimethoxyphenylacetic (S)-3-(L-alaninyl)amino-2 C-C 515.0 Dimethoxyphenylacetyl)-L- acid dihydro- 1-methyl-5-phenyl- 1Haianinyl)amino-2,3-dihydro- 1- (Aldrich) 1 ,4-benzodiazepin-2-one methyl-5-phenyl-1H-1 (Example 8-B) benzod 8C- 155 (S)-3-(L-alaninyl)amino-2,3- C-C 527.0 Methoxybenzoyl)propioiy Methoxybenzoyl)propionic dihydro-l1-methyl-S -pheny 1-1Halaninyl)amino-2,3-dihydro-1- acid I ,4-benzodiazepin-2-one 1H- 1,4- (Aldrich) (Example 8-B3) iazepi n-2-one 8C- 156 -(Thiophene-3-acetyl)- Thiophene-3 -acetic acid (S)-3-(L-alaninyl)amino-2 C-C 461.0 L-alaninyl)amino-2 ,3-dihydro- 1- (Acros) dihydro-l1-methyl-5-phenyl- 1Hmethyl-5-phenyl-1H- 1,4- 1 ,4-benzodiazepin-2-one benzodiazepin-2-one Example Compound Starting Material 1 Starting Material 2 General MS No. 8C- 157 '-(6-Phenylhexanoyl)-L- 6-Phenyl hexanoic acid (S)-3-(L-alaninyl)amino-2 3- C-C 511.2 alaninyl)amino-2 ,3-dihydro- 1- (Avocado) dihydro-1 -methyl-5-phenyl- 1Hmethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one 8-B3) 8C- 158 -(Isovaleryl)-L- Isovaleric acid (S)-3-(L-alaninyl)amino-2 C-C 420.8 alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-phenyl-l1Hmethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one iazepin-2-one 8-B3) 8C- 159 2,3 ,5 -Tri fluorophenylIacetic (S)-3-(L-alaninyl)amino-2 C-C 508.8 Trifluorophenylacetyl)-L- .acid dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1 (Fluorochem) 1 ,4-benzodiazepin-2-one methyl-5-plienyl-1IH- 1,4- (Example 8-B) benzodiazepin-2-one 8C- 160 2,4, 5-Trifluorophenylacetic (S)-3-(L-alaninyl)amino-2 C-C 509.0 Trifluorophenylacetyl)-L- acid dihydro-l1-methyl-5-phenyl- 1Halaninyl)aimino-2 ,3-d ihydro- 1- (Fluorochem) 1 ,4-benzodiazepin-2-one 1H-i (Example 8-B) benzodiazepin-2-one 8C- 161 -Adamantaneacetyl)- 1 -Adamantaneacetic acid (S)-3-(L-alaninyl)amino-2 C-C 513.2 L-alaninyl)amino-2,3-diliydro- 1 (Aldrich) dihydro-1 -methyl-5-phenyl- 1 Hmethyl-5-phenyl-1IH- 1,4- 1 ,4-benzodiazepin-2-one _______benzodiazepin-2-one -1 Example Compound Starting Material 1 Starting Material 2 General MIS No. _Procedure 8C- 162 Cyclohexanepentanoic acid (S)-3-(L-alaninyl)amino-2,3- C-C 503.0 (Cyclohexanepentanoyl)-L- (Aldrich) dihydro- 1-methyl-5-phenyl-l1Halaninyl)amino-2,3-dihydro-1 1 ,4-benzodiazepin-2-one methyl-5-phenyl-IH-1 (Example 8-B) benzod iazepin-2-one 8C- 163 '-(2-Thiopheneacetyl)-L- 2-Thiopheneacetic acid (S)-3-(L-phenylglycinyl)amino- C-C 523.0 phenylglycinyl)amino-2 (Aldrich) 2, 3-dihydro-l1-methyl-5-phenyldihydro-1 -methyl-5-phenyl-1H- 1 H-i ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one C-AA) 8C-164 3- (S)-3-(L-phenylglycinyl)amino- C-C 585.0 (Trifluoromethyl)phenylacetyl)- (Trifluoromethyl)phenylacet 2, 3-dihydro-l1-methyl-5-phenyl- L-phenylglycinyl)amino-2 ic acid 1 H-i ,4-benzodiazepin-2-one d ihydro-l1-methyl-5-phenyl-l1H- (Marshal Iton) (Example C-AA) I,4-benzodiazepin-2-one 8C-165 3,5-Difluorophenylacetic (S)-3-(L-phenylglycinyl)amino- C-C 553.0 Difluorophenylacetyl)-L- acid 2 ,3-dihydro-l1-methyl-5-phenylphenylglycinyl)amino-2, 3- (Aldrich) I H-i ,4-benzodiazepin-2-one 1H- (Example C-AA) 1 ,4-benzodiazepin-2-one 8C- 166 -(m-Tolylacetyl)-L- m-Tolylacetic acid (S)-3-(L-phenylglycinyl)amino- C-C 531.2 phenylglycinyl)amino-2 (Aldrich) 2 ,3-dihydro- 1 1H- 1 H-i ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one C-AA) Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C- 167 '-(3-Fluorophenylacetyl)- 3-Fluorophenylacetic acid (S)-3-(L-phenylglycinyl)amino- c-C 535.2 L-phenylglycinyl)amino-2 (Aldrich) 2, 3-dihydro-l1-methyl-5-phenyldihydro-l-methyl-5-phenyl-1 H- 1H- 1,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one (Example C-AA) 8C- 168 -(3-Bromophenylacetyl)- 3-Bromophenylacetic acid (S)-3-(L-phenylglycinyl)amino- C-C 595.2 L-phenylglycinyl)amino-2 (Aldrich) 2 ,3-dihydro-l1-methyl-5-phenyldihydro-l1-methyl-5-phenyl-l1H- lH- 1,4-benzodiazepin-2-one I ,4-benzodiazepin-2-one (Example C-AA) 8C-1 69 -(3-Chlorophenylacetyl)- 3-Chiorophenylacetic acid (S)-3-(L-phenylglycinyl)amino- C-C 551.2 L-phenylglycinyl)amino-2 (Aldrich) 2, 3-dihydro-l1-methyl-5-phenyl- 1H- lH-1 ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one (Example 8C- 170 3,4- (S)-3-(L-phenylglycinyl)amino- C-C 561.2 Methylenedioxyphenylacetyl)-L- Methylened ioxyphenyl]acetic 2 ,3-dihydro-l1-methyl-5-phenylphenylglycinyl)amino-2,3- acid 1H-1 ,4-benzodiazepin-2-one 1H- (Aldrich) (Example C-AA) 1 ,4-benzodiazepin-2-one 8C-171 Phenylmercaptoacetic acid (S)-3-(L-phenylglycinyl)amino- C-C 549.0 (Pheny lmercaptoacetyl)-L- (Aldrich) 2 ,3-dihydro- phenylglycinyl)amino-2, 3- 1 H-i ,4-benzodiazepin-2-one 1H- (Example C-AA) 1 ,4-benzodiazepin-2-one______________ Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-173 3,5- (S)-3-(L-phenylglycinyl)amino- C-C 653.0 Bis(trifluoromethyl)phenylacetyl Bis(trifluoromethyl)phenyla 2, 3-dihydro-l1-methyl-5-phenyl- )-L-phenylglycinyl)amino-2 cetic acid 1 H-I ,4-benzodiazepin-2-one IH- (Aldrich) (Example C-AA) I,4-benzodiazepin-2-one 8C- 174 '-((Methylthio)acetyl)-L- (Methylthio)acetic acid (S)-3-(L-phenylglycinyl)amino- C-C 487.2 phenylglycinyl)amino-2, 3- (Aldrich) 2, 3-dihydro-l1-methyl-5-phenyl- 1H- 1 H-i ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one (Example 8C- 175 '-(Phenoxyacetyl)-L- Phenoxyacetic acid (S)-3-(L-phenylglycinyl)amino- C-C 533.0 phenylglycinyl)amino-2 (Aldrich) 2, 3-dihydro- dihydro- 1-methyl-5-phenyl- 11- 1H-1 ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one (Example C-AA) 8C- 176 (S--N-(Phenylacetyl)-L- Phenylacetic acid (S)-3-(L-phenylgiycinyl)amino- C-C 517.2 phenylglycinyl)amino-2 (Aldrich) 2, 3-dihydro- 1 d ihydro- 1 -methyl-5-phenyl- 1 H- 1 H-i ,4-benzod iazepin-2-one 1 ,4-benzodiazepin-2-one C-AA) 8C- 177 -(Cyclohexylacetyl)-L- Cyclohexylacetic acid (S)-3-(L-phenylglycinyl)amino- C-C 523.2 phenylglycinyl)amino-2,3- (Aldrich) 2,3-dihydro- dihydro- 1-methyl.-5-phenyl-l1H- 1H- 1,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one C-AA) Example Compound Starting Material I Starting Material 2 General MS No. 8C-178 2,5-Difluorophenylacetic (S)-3-(L-phenylglycinyl)amino- c-C 553.0 Difluorophenylacetyl)-L- acid 2 ,3-dihydro-l1-methyl-5-phenylphenylglycinyl)amino-2 (Aldrich) 1 H-i ,4-benzodiazepin-2-one dihydro- 1 -methyl-5-phenyl- 1 H- (Example C-AA) 1 ,4-benzodiazepin-2-one 8C- 179 (S)-3-(N'-(Benzo thiophene-3- Benzo thiophene-3- (S)-3-(L-phenylglycinyl)amino- C-C 573.2 acetyl)-L-phenylglycinyl)amino- acetic acid 2 ,3-dihydro-l1-methyl-5-phenyl- 2 ,3-dihydro-l1-methyl-5-phenyl- (Aldrich) 1 H-i ,4-benzodiazepin-2-one 1 H-i ,4-benzodiazepin-2-one C-AA) 8C- 180 -(benzoylformyl)-L- Benzoylf'ormic acid (S)-3-(L-phenylglycinyl)amino- C-C 531.2 phenylglycinyl)amino-2 (Aldrich) 2 ,3-dihydro- dihydro- 1-methyl-5-phenyl- 1H- I H-i ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one (Example 8C-181 2,6-Difluorophenylacetic (S)-3-(L-phenylglycinyl)amino- C -C 553.0 Difluorophenylacetyl)-L- acid 2, 3-dihydro- phenylglycinyl)amino-2,3- (Aldrich) 1H-1 ,4-benzodiazepin-2-one dihydro- 1-methyl-5-phenyl- 1H- (Example C-AA) 1 ,4-benzodiazepin-2-one 8C-1 82 2,4-Di fluorophenylIacetic (S)-3-(L-phenylglycinyl)amino- C-C 553.0 Di tluorophenylacetyl)-L- acid 2, 3-dihydro-l1-methyl-5-phenylphenylglycinyl)amino-2, 3- (Aldrich) 1 H-i ,4-benzodiazepin-2-one dihydro-1-methyl-5-phenyl-1 H- (Example C-AA) 1 ,4-benzodiazepin-2-one I I_ Example Compound Starting Material 1 !Starting Material 2 General MS No. Procedure 8C- 183 3 ,4-Ditluorophenylacetic (S)-3-(L-phenylglycinyl)amino- C-C 553.0 Difluorophenylacetyl)-L- acid 2, 3-dihydro-l1-methyl-5-phenylphenylglycinyl)amino-2 (Aldrich) 1 H-i ,4-benzodiazepin-2-one dihydro- 1 -methyl-5-phenyl- I H- (Example C-AA) 1 ,4-benzodiazepin-2-one 8C- 184 '-(Butyryl)-L- Butyric acid (S)-3-(L-phenylglycinyl)amino- C-C 469.0 phenylglycinyl)amino-2,3- (Aldrich) 2,3-dihydro-l1-methyl-5-phenyldihydro-1 -methyl-5-phenyl- IH- 1 H-i ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one C-AA) 8C-185 (S)-3-(N'-(Heptanoyl)-L- Heptanoic acid (S)-3-(L-phenylglycinyl)amino- C-C 511.2 phenylglycinyl)amino-2 (Aldrich) 2 ,3-dihydro-l1-methyl-5-phenyl- 1 H- 11,4-benzodiazepin-2-one I ,4-benzodiazepin-2-one (Example C-AA) 8C- 186 -(4-(2-Thienyl)butyryl)- 4-(2-Thienyl)butyric acid (S)-3-(L-phenylglycinyl)amino- C-C 551.0 L-phenylglycinyl)amino-2 (Aldrich) 2, 3-dihydro-l1-methyl-5-phenyldihiydro-l1-methyl-5-phenyl-1 H- 1 H-i ,4-benzodiazepin-2-one I ,4-benzodiazepin-2-one 8C-1 87 -(5-Methyihexanoyl)-L- 5-Methyihexanoic acid (S)-3-(L-phenylglycinyl)amino- C-C 511.2 phenylglycinyl)amino-2 (Pfaltz and Bauer) 2 ,3-d ihydro- dihydro-1 -methyl-5-phenyl-1H- 1 H-i ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one (Example C-AA)
I__I
Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C- 188 '-(H~ydrocinnamyl)-L- Hydrocinnamic acid (S)-3-(L-phenylglycinyl)amino- C-C 531.2 phenyiglyciny l)amino-2 (Aldrich) 2, 3-dihydro-l1-methyl-5-phenyld ihydro-l1-methyl-5-phenyl-I- 1 H- 1-1,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one 8C-189 (S)-3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic acid (S)-3-(L-phenylglycinyl)amino- C-c 509.2 phenylglycinyl)amino-2 (Aldrich) 2, 3-dihydro-l1-methyl-5-phenyl- IH- 1H-1 ,4-benzodiazepin-2-one I ,4-benzodiazepin-2-one (Example 8C- 190 '-(Propionyl)-L- Propionic acid (S)-3-(L-phenylglycinyl)amino- C-C 455.0 phenylglycinyl)amino-2 (Aldrich) 2, 3-dihydro- dihydro-1-methyl-5-phenyl-1 H- 1 H-i ,4-benzodiazepin-2-one I ,4-benzodiazepin-2-one (Example C-AA) 8C- 191 3 ,4,5-Trifluorophenylacetic (S)-3-(L-phenylglycinyl)amino- C-C 571.0 Trifluorophenylacetyl)-L- acid 2 ,3-dihydro- 1 phenylglycinyl)amino-2, 3- (Fluorochem) 1 H-i ,4-benzodiazepin-2-one d ihydro- 1 -methyl-5-phenyl- 1 H- (Example C-AA) 1 ,4-benzodiazepin-2-one 8C- 192 (S)-3-(N-(4-Phenylbutyryl)-L- 4-Phenylbutyric acid (S)-3-(L-phenylglycinyl)amino- C-C 545.2 phenylglycinyl)amino-2,3- (Aldrich) 2,3-dihydro-l1-methyl-5-phenyl- 1H- 1 H-i ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C- 193 3-(N'-(2-Thiopheneacetyl)-L- 2-Thiopheneacetic acid 3-(L-alaninyl)amino-2,3- C-E 557.2 alaninyl)amino-2,3-dihydro-5- (Aldrich) dihydro-5-phenyl-l1-(4,4,4phenyl- 1 -(4,4,4-trifluorobutyl)- trifluorobutyl)-1H-1 ,4- 1 H-i ,4-benzod iazepin-2-one benzod iazepin-2-one 8C- 194 3-(N'-(2-Thiopheneacetyl)-L- 2-Thiopheneacetic acid 3-(L-alaninyl)amino-l1-(2-oxo-2- C-E 565.2 alaninyl)amino-l1-(2-oxo-2- (Aldrich) phenylethyl)-2 phenylethyl)-2,3-dihydro-5- phenyl- 1H-i ,4-benzod iazepin-2phenyl- 1H-i ,4-benzodiazepin-2- one one (Example C-AB) 8C-195 3-(N'-(2-Thiopheneacetyl)-L- 2-Thiopheneacetic acid 3-(L-alaninyl)amino-1I-methyl- C-E 468.1 alaninyl)amino-l1-methyl-2 (Aldrich) 2, 3-dihydro-5-(2-thiazolyl)- 1Hdihydro-5-(2-thiazolyl)- 1 H- 1,4- 1 ,4rbenzodiazepin-2-one benzodiazepin-2-one (Example C-AH) 8C-196 3-(N'-(2-Thiopheneacetyl)-L- 2-Thiopheneacetic acid 3-(L-alaninyl)amino-7-chloro- C-E 495.1 alaninyl)amino-7-chloro-2,3- (Aldrich) 2,3-dihydro-l1-methyl-5-phenyl- 1H- 1 H-I ,4-benzodiazepin-2-one I ,4-benzodiazepin-2-one (Example 8-C) 8C- 197 -(2-Thiopheneacetyl)-L- 2-Thiopheneacetic acid 3-(L-alaninyl)amino-7-chloro-5- C-F 529.1 alaninyl)amino-7-chloro-5-(2- (Aldrich) (2-chlorophenyl)-2 ,3-dihydro- 1- 531.1 chlorophenyl)-2,3-dihydro- 1 methyl-i H-i ,4-benzodiazepin-2methyl- I H-i ,4-benzodiazepin-2- one Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-198 3-(N'-(2-Thiopheneacetyl)-L- 2-Thiopheneacetic acid 3-(L-alaninyl)amino-5-(2- C-E 467.1 alaninyl)amino-5-(2-thienyl)-2 (Aldrich) thienyl)-2 ,3-dihydro- 1-methyldihydro-1-methyl-1H-1 1 H-i ,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-Al) 8C- 199 3-(N'-(2-Thiopheneacetyl)-L- 2-Thiopheneacetic acid 3-(L-alaninyl)amino-5 C-E 467.2 alaninyl)amino-5-cyclohexyl-2 (Aldrich) cyclohexyl-2, 3-dihydro- 1dihydro-1-methyl-1H-1 methyl-I H-i ,4-benzodiazepin-2benzodiazepin-2-one one (Example 8-G) 8C-200 3-(N'-(2-Thiopheneacetyl)-L- 2-Thiopheneacetic acid 3-(L-alaninyl)amino-7-bromo-5- C-E 557.1 alaninyl)amino-7-bromo-5-(2- (Aldrich) (2-fluorophenyl)-2 ,3-dihydro- 1- 559.1 fluorophenyl)-2 ,3-dihydro-1- methyl-I H-I ,4-benzodiazepin-2methyl-1H-l ,4-benzodiazepin-2- one -one _(Exam ple 8-D 8C-201 N'-(2-Thiopheneacetyl)-L- 2-Thiopheneacetic acid 3-(L-alaninyl)-amino-)-2,4- C-E 527.3 alaninyl)-amino-)-2 ,4-dioxo- 1,5- (Aldrich) d joxo- 1, 5-bis-(2 ,2bis-(2,2-dimethylpropyl)-2,3 dimethylpropyl)-2,3 tetrahydro- 11-1,5- tetrahydro-1H-1 benzodiazepine benzodiazepine (Example_8-V) Example Compound Starting Material 1 Starting Material 2 General MS No. 8C-202 ,5-Difluorophenylacetyl)- 3 ,5-Difluorophenylacetic 3-(L-alaninyl)amino-2,3- C-E 587.2 L-alaninyl)amino-2 ,3-dihydro-5- acid dihydro-5-phenyl-l1-(4,4,4phenyl-l1-(4,4,4-trifluorobutyl)- (Aldrich) trifluorobutyl)- 1 H- 1,4- 1 H-i ,4-benzod iazepin-2-one benzodiazepin-2-one
C-AC)
8C-203 3-(N 5-Difluorophenylacetyl)- 3 ,5-Difluorophenylacetic 3-(L-alaninyl)amino-l1-(2-oxo-2- C-E 595.2 L-alaninyl)amino-l1-(2-oxo-2- acid phenylethyl)-2 phenylethyl)-2 ,3-dihydro-5- (Aldrich) phenyl- 1H-i ,4-benzodiazepin-2phenyl- 1H-i ,4-benzodiazepin-2- one one 8C-204 3-(N 5-Difluorophenylacetyl)- 3 ,5-Difluorophenylacetic 3-(L-alaninyl)amino- 1-methyl- C-E 498.1 L-alaninyl)amiino- I-methyl-2,3- acid 2,3-dihydro-5-(2-thiazolyl)- 1Hdihydro-5-(2-thiazolyl)- IH- 1,4- (Aldrich) I ,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AU) 8C-205 3 ,5-Difluorophenylacetyl)- 3 ,5-Difluorophenylacetic 3-(L-alaninyl)amino-7-chloro- C-E 525.2 L-alaninyl)amino-7-chloro-2,3- acid 2, 3-dihydro-l1-methyl-5-phenyl- IiH- (Aldrich) I H-I ,4-benzod iazepin-2-one 1 ,4-benzodiazepin-2-one (Example 8-C) 8C-206 -Difluorophenylacetyl)- 3 ,5-Difluorophenylacetic 3-(L-alaninyl)amino-7-chloro-5- C-E 559.1 L-alaninyl)amino-7-chloro-5-(2- acid (2-chlorophenyl)-2 ,3-dihydro- 1 561.1 chlorophenyl)-2 ,3-dihydro- 1- (Aldrich) methyl-i H-i ,4-benzodiazepin-2methyl-1H-1 ,4-benzodiazepin-2- one one Example Compound Starting Material 1 Starting Material 2 General MIS No. 8C-207' 3-(N 5-Difluorophenylacetyl)- 3 ,5-Difluorophenylacetic 3-(L-alaninyl)amino-5-(2- C-E 497.1 L-alaninyl)amino-5-(2-thienyl)- acid thienyl)-2 ,3 -dihydro- 1-methyl- 2,3-dihydro-1 -methyl-i H- 1,4- (Aldrich) IH-1I,4-benzodiazepin-2-one benzodiazepin-2-one C-Al) 8C-208 3-(N ,5-Difluorophenylacetyl)- 3 ,5-Difluorophenylacetic 3-(L-alaninyl)amino-5- C-E 497.2 acid cyclohexyl-2 ,3-dihydro- 1- 2, 3-dihydro- 1-methyl-i H- 1,4- (Aldrich) methyl-i H-i ,4-benzodiazepin-2benzod iazepin-2-one one (Example 8-G) 8C-209 3-(N 5-Difluorophenylacetyl)- 3 ,5-Difluorophenylacetic 3 -(L-alaninyl)amino-7-bromo-5- C-E 587.1 L-alaninyl)amino-7-bromo-5-(2- acid (2-fluorophenyl)-2 ,3-dihydro- 1- 590.1 fluorophenyl)-2 ,3-dihydro- 1- (Aldrich) methyl-I H-i ,4-benzodiazepin-2methyl-iH- 1,4-benzodiazepin-2- one one 8C-210 3,5-Difluorophenylacetic 3-(L-alaninyl)-amino-)-2,4- C-E 557.3 Difluorophenylacetyl)-L- acid dioxo-i ,5-bis-(2,2alaninyl)-amino-)-2 ,4-dioxo- 1,5- (Aldrich) dimethylpropyl)-2 ,3,4,5bis-(2,2-dimethylpropyl)-2,3 tetrahydro-iH-i tetrahydro-iH-i benzodiazepine I_ benzodiazepine (Example Example Compound Starting Material 1 Starting Material 2 General MS No. 8C-2 11 3('-(3-Fluorophenylacety 3-Fluorophenylacetic acid 3-(L-alaninyl)amino-2 C-E 569.2 alaninyl)amino-2 ,3 -dihydro-5- (Aldrich) dihydro-5 -phenyl-l1-(4,4,4phenyl- 1 -(4,4,4-trifluorobutyl)- trifluorobutyl)- 1 H- 1,4- 1 H-i ,4-benzodiazepin-2-one benzodiazepin-2-one 8C-2 12 3-(N '-(3-Fluorophenylacetyl)-L- 3-Fluorophenylacetic acid 3-(L-alaninyl)amino-l1-(2-oxo-2- C-E 577.2 alaninyl)amino- 1-(2-oxo-2- (Aldrich) phenylethyl)-2 ,3-dihydro-5 phenylethyl)-2 ,3-dihydro-5- phenyl- 1H-i ,4-benzodiazepin-2phenyl-1H-1 ,4-benzodiazepin-2- one 8C-2 13 3-(N '-(3-Fluorophenylacetyl)-L- 3 -Fluorophenylacetic acid 3-(L-alaninyl)amino-l1-methyl- C-E 480.1 alaninyl)amino- 1-methyl-2,3- (Aldrich) 2,3-dihydro-5-(2-thiazolyl)- 1Hdihydro-5-(2-thiazolyl)-1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AH) 8C-2 14 -(3-Fluorophenylacetyl)-L- 3-Fluorophenylacetic acid 3-(L-alaninyl)amino-7-chloro- C-E 507.2 alaninyl)amino-7-chloro-2 (Aldrich) 2 ,3-dihydro- 1 1 H- 11,4-benzodiazepin-2-one I,4-benzodiazepin-2-one (Example 8-C) 8C-2 15 3-(N '-(3-Fluorophenylacetyl)-L- 3-Fluorophenylacetic acid 3-(L-alaninyl)amino-7-chloro-5- C-E 541.1 alaninyl)amino-7-chloro-5-(2- (Aldrich) (2-chlorophenyl)-2 ,3-dihydro- 1- 543.1 chlorophenyl)-2,3-dihydro- 1- methyl-1H-1 ,4-benzodiazepin-2methyl- LH- 1,4-benzodiazepin-2- one Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-2 16 3-N-(3-Fluorophenylacetyl)-L- 3-Fluorophenylacetic acid 3-(L-alaninyl)amino-5-(2- C-E 479.1 alaninyl)amino-5-(2-thienyl)-2 (Aldrich) thienyl)-2 ,3-d ihydro- 1-methyldihydro-i-methyl- IH-i ill-i,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-Al) 8C-2 17 3('-(3-Fluorophenylacetyl)-L- 3-Fluorophenylacetic acid 3-(L-alaninyl)amino-5- C-E 479.2 alaninyl)amino-5-cyclohexyl-2,3- (Aldrich) cyclohexyl-2,3-dihydro- 1dihydro-i-methyl-1H- 1,4- methyl- Ill-i ,4-benzodiazepin-2benzodiazepin-2-one one 8-G) 8C-2 18 -(3-Fluorophenylacetyl)-L- 3 -Fluorophenylacetic acid 3-(L-alaninyl)amino-7-bromo-5- C-E 571.1 alaninyl)amino-7-bromo-5-(2- (Aldrich) (2-fluorophenyl)-2, 3-dihydro- 1- 573.1 fluorophenyl)-2,3-dihydro- 1- methyl-i H-i ,4-benzodiazepin-2methyl-i H-I ,4-benzodiazepin-2- one one (Example 8-D) 8C-2 19 N'-(3-Fluorophenylacetyl)-L- 3-Fluorophenylacetic acid 3-(L-alaninyl)-amino-)-2 C-E 539.3 alaninyl)-amino-)-2 ,4-dioxo- 1,5- (Aldrich) dioxo- 1, 5-bis-(2 ,2bis-(2 ,2-dimethylpropyl)-2,3 dimethylpropyl)-2 ,3 tetrahydro-iH-i tetrahydro-1H-i benzodiazepine, benzodiazepine ____(Example_8-V)_ Example Compound Starting Material I Starting Material 2 General MS No. 8C-220 -(Methyltliio)acetyl)-L- (Methylthio)acetic acid 3-(L-alaninyl)amino-2 C-E 521.2 alaninyl)amino-2 ,3-dihydro-5- (Aldrich) dihydro-5-phenyl-l1-(4,4,4phenyl- 1 ,4-trifluorobutyl)- trifluorobutyl)- 1 H-i 1,4- 1 H-i ,4-benzodiazepin-2-one benzodiazepin-2-one
C-AC)
8C-22 1 -(Methylthio)acetyl)-L- (Methylthio)acetic acid 3-(L-alaninyl)amino- 1-(2-oxo-2- C-E 529.2 alaninyl)amnino- 1-(2-oxo-2- (Aldrich) phenylethyl)-2 phenylethyl)-2 ,3-dihydro-5- phenyl- 1H-i ,4-benzodiazepin-2phenyl-i H-i ,4-benzodiazepin-2- one 8C-222 3' -(Methylthio)acetyl)-L- (Methylthio)acetic acid 3-(L-alaninyl)amino- i-methyl- C-E 432.1 alaninyl)amino-l1-methyl-2 (Aldrich) 2 ,3-dihydro-5-(2-thiazolyl)-i Hdihydro-5-(2-thiazolyl)- 1H-i 1 ,4-benzodiazepin-2-one _______benzodiazepin-2-one (Example 8C-223 3-(N'-(Methylthio)acetyl)-L- (Methylthio)acetic acid 3-(L-alaninyl)amino-7-chloro- C-E 459.1 alaninyl)amino-7-chloro-2 (Aldrich) 2, 3-dihydro-l1-methyl-5-phenyldihydro- I-methyl-5-phenyl- 1H- I H-i ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one (Example 8-C) 8C-224 -(Methylthio)acetyl)-L- (Methylthio)acetic acid 3-(L-alaninyl)amino-7-chloro-5- C-E 493.1 alaninyl)amino-7-chloro-5-(2- (Aldrich) (2-chlorophenyl)-2 ,3-dihydro- 1- 495.1 chlorophenyl)-2,3-dihydro- 1- methyl-i H-i ,4-benzodiazepin-2methyl- 1H- 1,4-benzodiazepin-2- one Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-225 3-(N'-(Methylthio)acetyl)-L- (Methylthio)acetic acid 3-(L-alaninyl)amino-5-(2- C-E 431.1 alaninyl)amino-5-(2-thienyl)-2 (Aldrich) thienyl)-2 ,3-dihydro- 1-methyldihydro-1-methyl-1H-1 Il-i 1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-Al) 8C-226 3-(N '-(Methylthio)acetyl)-L- (Methylthio)acetic acid 3-(L-alaninyl)amino-5- C-E 431.2 alaninyl)amino-5-cyclohexyl-2 (Aldrich) cyclohexyl-2 ,3-dihydro- 1dihydro-1-methyl-iH-1 methyl-ill-i,4-benzodiazepin-2benzodiazepin-2-one one 8-G) 8C-227 3-(N'-(Methylthio)acetyl)-L- (Methylthio)acetic acid 3-(L-alaninyl)amino-7-bromo-5- C-E 521.1 alaninyl)amino-7-bromo-5-(2- (Aldrich) (2-fluorophenyl)-2 ,3-dihydro- 1- 523.1 fluorophenyl)-2 ,3-dihydro- 1- methyl-i H-i ,4-benzod iazepin-2methyl-i H-i ,4-benzodiazepin-2- one one 8-D) 8C-228 N' -(Methylthio)acetyl)-L- (Methylthio)acetic acid 3-(L-alaninyl)-amino-)-2 C-E 491.3 alaninyl)-amino-)-2,4-dioxo- 1,5- (Aldrich) dioxo- 1,5-bis-(2 ,2bis-(2,2-dimethylpropyl)-2 ,3 dimethylpropyl)-2,3 tetrahydro-1H-1 tetrahydro-iH-i benzodiazepine benzodiazepine, ___(Example_8-V)_ Example Compound Starting Material 1 Starting Material 2 General MIS No. 8C-229 3-(N'-(Phenylacetyi)-L- Phenylacetic acid 3-(L-alaninyl)amino-2,3- C-E 551 .2 alaninyl)amino-2 ,3-dihydro-5- (Aldrich) dihydro-5-phenyl-l1-(4,4,4phenyl-l1-(4,4,4-trifluorobutyl)- trifluorobutyl)- 1H- 1,4- 1 H-i ,4-benzodiazepin-2-one benzodiazepin-2-one 8C-230 -(Phenylacetyl)-L- Phenylacetic acid 3-(L-alaninyl)amino- 1-(2-oxo-2- C-E 559.5 alaninyl)amino-1-(2-oxo-2- (Aldrich) phenylethyl)-2 phenylethyl)-2 ,3-dihydro-5- phenyl- 1H-i ,4-benzodiazepin-2phenyl-1H-1 ,4-benzodiazepin-2- one (Example C-AB) 8C-23 1 3-(N '-(Phenylacetyl)-L- Phenylacetic acid 3-(L-alaninyl)amino- 1-methyl- C-E 462.2 alaninyl)amino-i1-methyl-2,3- (Aldrich) 2,3-dihydro-5-(2-thiazolyl)- 1Hdihydro-5-(2-thiazolyl)-l1H- 1,4- 1 ,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8C-232 3-(N'-(Phenylacetyl)-L- Phenylacetic acid 3-(L-alaninyl)amino-7-chloro- C-E 489.2 alaninyl)amino-7-chloro-2 (Aldrich) 2, 3-dihydro-l1-methyl-5-phenyl- IH- 1 H-i ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one 8C-233 3-(N '-(Phenylacetyl)-L- Phenylacetic acid 3-(L-alaninyl)amino-7-chloro-5 C-E 523.1 alaninyl)amino-7-chloro-5-(2- (Aldrich) (2-chlorophenyl)-2 ,3-dihydro- 1 525.1 chiorophenyl)-2,3-dihydro- 1- methyl- ILH- 1,4-benzodiazepin-2methyl-i H-i ,4-benzodiazepin-2- one (Example Example Compound Starting Material I Starting Material 2 General MS No. 8C-234 3-(N'-(Phenylacetyl)-L- Phenylacetic acid 3-(L-alaninyl)amino-5-(2- C-E 461.1 alaninyl)amino-5-(2-thienyl)-2 (Aldrich) thienyl)-2 ,3-dihydro- 1-methyldihydro-i-methyl-1H-i 1 H-I ,4-benzodiazepin-2-one benzod iazepin-2-one (Example C-Al) 8C-235 3-(N'-(Phenylacetyl)-L- Phenylacetic acid 3-(.L-alaninyl)amino-5- C-E 461.2 alaninyl)amino-5-cyclohexyl-2 (Aldrich) cyclohexyl-2 ,3-dihydro- 1dihydro- 1-methyl-i H- 1,4- methyl-i H-i ,4-benzodiazepin-2benzodiazepin-2-one one 8-G) 8C-236 3-(N '-(Phenylacetyl)-L- Phenylacetic acid 3-(L-alaninyl)amino-7-bromo-5 C-E 553.1 alaninyl)amino-7-bromo-5-(2- (Aldrich) (2-fluorophenyl)-2 ,3-dihydro- 1- 554.1 fluorophenyl)-2,3-dihydro-i methyl-1H-1 ,4-benzodiazepin-2methyl-i H-i ,4-benzodiazepin-2- one _____(Example 8-D) 8C-237 Phenylacetyl)-L- Phenylacetic acid 3-(L-alaninyl)-amino-)2,4- C-E 521.3 alaninyl)-amino-)2 ,4-dioxo- 1,5- (Aldrich) dioxo- 1,5-bis-(2 ,2bis-(2,2-dimethylpropyl)-2,.3,4,5- dimethylpropyl)-2 ,3 tetrahydro-IH-i tetrahydro-IH-i benzodiazepine, benzodiazepine ___(Example_8-V)_ Example Compound Starting Material 1 Starting Material 2 General MIS No. Procedure 8C-238 3-(N'-(Benzoylformyl)-L- Benzoylformic acid 3-(L-alaninyl)amino-2,3- C-E 565.2 alaninyl)amino-2 ,3-dihydro-5- (Aldrich) dihydro-5-phenyl-l1-(4,4,4phenyl- 1 -(4,4,4-trifluorobutyl)- trifluorobutyl)- 1 H- 1,4- 1 H-i ,4-benzod iazepin-2-one benzodiazepin-2-one (Example C-AC) 8C-239 3-(-(Benzoylformyl)-L- Benzoylformic acid 3 -(L-alaninyl)amino-l1-(2-oxo-2- C-E 573.2 alaninyl)amino-l1-(2-oxo-2- (Aldrich) phenylethyl)-2 phenylethyl)-2 ,3-dihydro-5- phenyl- 1H-i ,4-benzodiazepin-2phenyl- 1H-i ,4-benzodiazepin-2- one (Example C-AB) 8C-240 -(Benzoylformyl)-L- Benzoylformic acid 3-(L-alaninyl)amino- 1-methyl- C-E 476.1 aiariinyl)amino- 1-methyl-2 (Aldrich) 2 ,3-dihydro-5-(2-thiazolyl)- 1Hdihydro-5-(2-thiazolyl)-1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one 8C-24 1 -(Benzoylformyl)-L- Benzoylformic acid 3-(L-alaninyl)amino-7-chloro- C-E 503.1 alaninyl)amino-7-chloro-2 (Aldrich) 2, 3-dihydro-l1-methyl-5-phenyldihydro- 1 -methyl-5-phenyl- I H- 1 H-i ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one 8C-242 3('-(Benzoylformyl)-L- Benzoylformic acid 3-(L-alaniny l)amino-7-chloro-5- C-E 537.1 alaninyi)amino-7-chloro-5-(2- (Aldrich) (2-chlorophenyl)-2 ,3-dihydro- 1- 539.1 chlorophenyl)-2,3-dihydro- 1- methyl-i H-i ,4-beiizodiazepin-2methyl-i H-i ,4-benzodiazepin-2- one Example Compound Starting Material 1 Starting Material 2 General MS No. 8C-243 3('-(Benzoylformyl)-L- Benzoylformic acid 3-(L-alaninyl)amino-5-(2- C-E 475.1 alaninyl)amino-5-(2-thienyl)-2 (Aldrich) thienyl)-2 ,3-dihydro- 1-methyldihydro-1-methyl-1H-1 IH-1 ,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-Al) 8C-244 3('-(Benzoylformnyl)-L- Benzoylformic acid 3 -(L-alaninyl)amino-5- C-E 475.2 alaninyl)amino-5-cyclohexyl-2 (Aldrich) cyclohexyl-2 ,3-dihydro- 1 dihydro-1-methyl-1H-1 methyl-i H-i ,4-benzodiazepin-2benzodiazepin-2-one one 8-G) 8C-245 3-(N'-(Benzoylformyl)-L- Benzoylformic acid 3-(L-alaninyl)amino-7-bromo-5- C-E 567.1 alaninyl)amino-7-bromo-5-(2- (Aldrich) (2-fluorophenyl)-2 ,3-dihydro- 1- 568.1 fluorophenyl)-2,3-dihydro- 1 methyl-1 H- 1,4-benzodiazepin-2methyl-1IH- 1,4-benzodiazepin-2- one one (Example 8-D) 8C-246 N'-(Benzoylformyl)-L- Benzoylformic acid 3-(L-alaninyl)-amino-)-2,4- C-E 535.3 alaninyi)-amino-)-2,4-dioxo- 1,5- (Aldrich) dioxo- 1,5-bis-(2,2bis-(2,2-dimethylpropyl)-2,3 dimethylpropyl)-2,3 tetrahydro-1H-1 tetrahydro-1H-1 benzodiazepine benzodiazepine 8-V) Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-247 3('-(Butyryl)-L- Butyric acid 3-(L-alaninyl)amino-2 C-E 503.2 alaninyl)amino-2 ,3-dihydro-5- (Aldrich) dihydro-5-phenyl-l1-(4,4,4phenyl- 1 ,4,4-trifluorobutyl)- trifluorobutyl)- 1H- 1,4- 1 H-i ,4-benzodiazepin-2-one benzodiazepin-2-one ___(ExampleC-AC)_ 8C-248 3-(N'-(Butyryl)-L- Butyric acid 3-(L-alaninyl)amino- 1-(2-oxo-2- C-E 511.2 alaninyl)amino-l1-(2-oxo-2- (Aldrich) phenylethyl)-2 phenylethyl)-2 ,3-dihydro-5- phenyl- 111- 1,4-benzodiazepin-2phenyl-1IH- 1,4-benzodiazepin-2- one one 8C-249 3-(N'-(Butyryl)-L- Butyric acid 3-(L-alaninyl)amino-l-methyl- C-E 414.1 alaninyl)amino- 1 -methyl-2 (Aldrich) 2, 3-dihydro-5-(2-thiazolyl)- I Hdihydro-5-(2-thiazolyl)-1 H- 1,4- 1 ,4-benzodiazepin-2-one benzodiazepin-2-one C-AH) 8C-250 3-(N'-(Butyryl)-L- Butyric acid 3-(L-alaninyl)amino-7-chloro- C-E 441.2 alaninyl)amino-7-chloro-2,3- (Aldrich) 2, 3-dihydro- 1H- 1 H-i ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one (Example 8C-25 1 3-(N'-(Butyryl)-L- Butyric acid 3-(L-alaninyi)amino-7-chloro-5- C-B 475.1 alaninyl)amino-7-chloro-5-(2- (Aldrich) (2-chlorophenyl)-2,3-dihydro- 1- 477.1 chlorophenyl)-2 ,3-dihydro-1 methyl-1H-1 ,4-benzodiazepin-2methyl-i H-i ,4-benzodiazepin-2- one ______(Example 8-F) Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-252 3-(N'-(Butyryl)-L- Butyric acid 3-(L-alaninyl)amino-S-(2- C-E 413.1 alaninyl)amino-5-(2-thienyl)-2 (Aldrich) thienyl)-2 ,3-dihydro- 1-methyldihydro-1 -methyl- 1H- 1 H-i,4-benzodiazepin-2-one benzodiazepin-2-one C-Al) 8C-253 3-(N'-(Butyryl)-L- Butyric acid 3-(L-alaninyl)amino-5- C-E, 413.2 alaninyl)amino-5-cyclohexyl-2 (Aldrich) cyclohexyl-2 ,3-dihydro- 1dihydro-1-methyl-1H-1 methyl-i H-i ,4-benzodiazepin-2benzodiazepin-2-one one (Example 8-G) 8C-254 3-(N'-(Butyryl)-L- Butyric acid 3-(L-alaninyl)amino-7-bromo-5- C-E, 503.1 alaninyl)amino-7-bromo-5-(2- (Aldrich) (2-fluorophenyl)-2 ,3-dihydro- 1- 506.1 fluorophenyl)-2 ,3-dihydro- 1- methyl-1H-1 ,4-benzodiazepin-2methyl-1IH- 1,4-benzodiazepin-2- one one (Example 8-D) 8C-255 N' -(Butyry I)-L-alaninyl)- Butyric acid 3-(L-alaninyl)-amino-)-2 C-E 473.3 amino-)-2 ,4-dioxo-1I,5-bis-(2 (Aldrich) dioxo- 1,5-bis-(2 ,2dimethylpropyl)-2,3 dimethylpropyl)-2 ,3 tetrahydro-lH-1 tetrahydro-1H-1 benzodiazepine benzodiazepine ___(Example_8-V) Example Compound Starting Material 1 Starting Material 2 General MS No. 8C-256 3-(N '-(4-(2-Thienyl)butyryl)-L- 4-(2-Thienyl)butyric acid 3-(L-alaninyl)amino-2,3- C-E 585.2 alaninyl)amnino-2,3-dihydro-5- (Aldrich) dihydro-5-phenyl-l1-(4,4,4phenyl-l1-(4 ,4,4-trifluorobutyl)- trifluorobutyl)-1H-i ,4- 1 H-i ,4-benzodiazepin-2-one benzodiazepin-2-one 8C-257 3-(N'-(4-(2-Thienyl)butyryl)-L- 4-(2-Thienyl)butyric acid 3-(L-alaninyl)amino-l1-(2-oxo-2- C-E 593.2 alaninyl)amino-l1-(2-oxo-2- (Aldrich) phenylethyl)-2 phenylethyl)-2 ,3-dihydro-5- phenyl- IH-I ,4-benzodiazepin-2phenyl- 1H-i ,4-benzodiazepin-2- one one (Example C-AB) 8C-258 -(4-(2-Thienyl)butyryl)-L- 4-(2-Thienyl)butyric acid 3-(L-alaninyl)amino- 1 -methyl- C-E 496.1 alaninyl)amino- 1 -methyl-2 (Aldrich) 2, 3-dihydro-5-(2-thiazolyl)- 1Hdihydro-5-(2-thiazolyl)-1IH- 1,4- I ,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AH) 8C-259 3 -(4-(2-Thienyl)butyryl)-L- 4-(2-Thienyl)butyric acid 3-(L-alaninyl)amino-7-chloro- C-E 523.2 alaninyl)amino-7-chloro-2 (Aldrich) 2, 3-dihydro-i1-methyl-5-phenyldihydro-1 -methyl-5-phenyl- 1H- 1 H-i ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one (Example 8-C) 8C-260 3 '-(4-(2-ThienyI)butyry 4-(2-Thienyl)butyric acid 3-(L-alaninyl)amino-7-chloro-5 C-E 557.1 alaninyl)amino-7-chloro-5-(2- (Aldrich) (2-chlorophenyl)-2 ,3-dihydro- 1- 559.1 chlorophenyl)-2,3-dihydro- 1 methyl-i H-i ,4-benzodiazepin-2methyl-ill-i,4-benzodiazepin-2- one 8-F) Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-26 1 -(4-(2-Thienyl)butyryl)-L- 4-(2-Thienyl)butyric acid 3-(L-alaninyl)amino-5-(2- C-E 495.1 -(2-thienyl)-2 (Aldrich) thienyl)-2 ,3-dihydro-l1-methyldihydro-1-methyl-1H-1 1 H-i ,4-benzodiazepin-2-one benzodiazepin-2-one C-Al) 8C-262 3-(N'-(4-(2-Thienyl)butyryl)-L- 4-(2-Thienyl)butyric acid 3-(L-alaninyl)amino-5- C-E 495.2 alaninyl)amino-5-cyclohexyl-2 (Aldrich) cyclohexyl-2,3-dihydro- 1dihydro-1-methyl-1H-1 methyl-i H-i ,4-benzodiazepin-2benzodiazepin-2-one 'one ___(Example_8-G) 8C-263 3-(N '-(4-(2-Thienyl)butyryl)-L- 4-(2-Thienyl)butyric acid 3-(L-alaninyl)amino-7-bromo-5- C-E 585.1 alaninyl)amino-7-bromo-5-(2- (Aldrich) (2-fluorophenyl)-2 ,3-dihydro- 1- 587.1 fluorophenyl)-2 ,3-dihydro-1 methyl- I H-i ,4-benzodiazepin-2methyl- 1 H-i ,4-benzodiazepin-2- one (Example 8-D) 8C-264 3 N'-(4-(2-Thienyl)butyryl)-L- 4-(2-Thienyl)butyric acid 3-(L-alaninyl)-amino-)-2 C-E 555.3 alaninyl)-amino-)-2 ,4-dioxo- 1,5- (Aldrich) dioxo- 1,5-bis-(2,2bis-(2,2-dimethylpropyl)-2,3 dimethylpropyl)-2,3 tetrahydro-1H-1 tetrahydro-1H-1 benzodiazepine benzodiazepine ___(Example_8-V) Example Compound Starting Material 1 Starting Material 2 General MIS No. 8C-265 -(Cyclopentylacetyl)-L- Cyclopentylacetic acid 3-(L-alaninyl)amino-2 ,3 C-E 543.3 alaninyl)amino-2 ,3-dihydro-5- (Aldrich) dihydro-5-phenyl-l1-(4,4,4phenyl- 1 -(4,4,4-trifluorobutyl)- trifluorobutyl)- 1 H- 1,4- 1 H-i ,4-benzodiazepin-2-one benzodiazepin-2-one ___(ExampleC-AC)_ 8C-266 3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic acid 3-(L-alaninyl)amino-l1-(2-oxo-2- C-F 551.3 alaninyl)amino- 1-(2-oxo-2- (Aldrich) phenylethyl)-2 phenylethyl)-2 ,3-dihydro-5- phenyl- 1H-i ,4-benzodiazepin-2phenyl-LH- 1,4-benzodiazepin-2- one (Example C-AB) 8C-267 -(Cyclopentylacetyl)-L- Cyclopentylacetic acid 3-(L-alaninyl)amino- 1 -methyl- C-E 454.2 alaninyl)amino-l1-methyl-2 (Aldrich) 2 ,3-dihydro-5-(2-thiazolyl)- 1 Hdihydro-5-(2-thiazolyl)- 1H- 1,4- 1 ,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AH) 8C-268 3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic acid 3-(L-alaninyl)amino-7-chloro- C-E 481.2 alaninyl)amino-7-chloro-2 (Aldrich) 2 ,3-dihydro-l1-methyl-5-phenyldihydro- 1-methyl-5-phenyl- lH- 1 H-i ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one 8C-269 3 -(Cyclopentyiacetyl)-L- Cyclopentylacetic acid 3-(L-alaninyl)amino-7-chloro-5- C-E 515.2 alaninyl)amino-7-chloro-5-(2- (Aldrich) (2-chlorophenyl)-2 ,3-dihydro- 1- 517.2 chlorophenyl)-2,3-dihydro- I methyl-i H-i ,4-benzodiazepin-2methyl-I H-i ,4-benzodiazepin-2- one ______(Example 8-F) Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-270 -(Cyclopentylacetyl)-L- Cyclopentylacetic acid 3-(L-alaninyl)amino,-5-(2- C-E 453.1 alaninyl)amino-5-(2-thienyl)-2 (Aldrich) thienyl)-2 ,3-dihydro- i-methyldihydro-i-methyl-1H-1 1 H-i ,4-benzodiazepin-2-one benzod iazepin-2-one C-Al) 8C-271 3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic acid 3-(L-alaninyl)amino-5- C-E 453.3 alaninyl)amino-5-cyclohexyl-2 (Aldrich) cyclohexyl-2 ,3-dihydro- 1dihydro-i-methyl-iH-1 methyl-ill-i,4-benzodiazepin-2benzodiazepin-2-one one (Example 8-G) 8C-272 3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic acid 3-(L-alaninyl)amino-7-bromo-5- C-E 543.1 alaninyl)amino-7-bromo-5-(2- (Aldrich) (2-fluorophenyl)-2 ,3-dihydro- 1- 546.1 fluorophenyl)-2 ,3-dihydro- 1- methyl-ill-i,4-benzodiazepin-2methyl-i H-i ,4-benzodiazepin-2- one one (Example 8-D) 8C-273 N' Cyclopentylacetyl)-L- Cyclopentylacetic acid 3-(L-alaninyl)-amino-)-2 C-E 513.3 alaninyl)-amino-)-2 ,4-dioxo- 1,5- (Aldrich) dioxo-1 ,5-bis-(2,2bis-(2 ,2-dimethylpropyl)-2 dimethylpropyl)-2,3 tetrahydro- 1H-i,5- tetrahydro-1H-i benzodiazepine benzodiazepine, ___(Example_8-F)_ Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-274 3-(N 3-(Trifluoromethyl)butyric 3-(L-alaninyl)amino-2 C-E 571.2 (Trifluoromethyl)butyryl)-L- acid dihydro-5-phenyl-l1-(4,4,4alaninyl)amino-2 ,3-dihydro-5- (Fluorochem) trifluorobutyl)- 1H- 1,4phenyl-l1-(4,4 ,4-trifluorobuty benzod iazepin-2-one 1H-l ,4-benzodiazepin-2-one (Example C-AC) 8C-275 3-(Trifluoromethyl)butyric 3-(L-alaninyl)amino-l1-(2-oxo-2- C-E 579.2 (Trifluoromethyl)butyryl)-L- acid phenylethyl)-2 alaninyl)amino- 1 -(2-oxo-2- (Fluorochem) phenyl- 1 H-i ,4-benzod iazepin-2phenylethyl)-2 ,3-dihydro-5- one phenyl- 1H-i ,4-benzodiazepin-2- (Example C-AB) one 8C-276 3-(N 3-(Trifluoromethyl)butyric 3-(L-alaninyl)amino-1 -methyl- C-E 482.1 (Triluoromethyl)butyryl)-L- acid 2, 3-dihydro-5-(2-thiazolyl)-l1Halaninyl)amino- 1-methyl-2 (Fluorochem) 1 ,4-benzodiazepin-2-one dihydro-5-(2-thiazolyl)- 1H- 1,4- (Example C-AH) benzodiazepin-2-one 8C-277 3-(Trifluoromethyl)butyric 3-(L-alaninyl)amino-7-chloro- C-E 509.1 (Trifluoromethyl)butyryl)-L- acid 2, 3-dihydro-l1-methyl-5-phenylalaninyl)amino-7-chloro-2 (Fluorochem) 1 H-I ,4-benzodiazepin-2-one dihydro- 1-methyl-5-phenyl- 1H- (Example 8-C) I_ 1 ,4-benzodiazepin-2-one I I I I I Example Compound Starting Material 1 Starting Material 2 General MIS No. Procedure 8C-278 3-(N 3-(Trifluoromethyl)butyric 3-(L-alaninyl)amino-7-chloro-5- C-E 543.1 (Trifluoromethyl)butyryl)-L- acid (2-chlorophenyl)-2 ,3-dihydro- 1 545.1 alaninyl)amino-7-chloro-5-(2- (Fluorochem) methyl-i H-i ,4-benzodiazepin-2chlorophenyl)-2 ,3-dihydro- 1- one methyl-iH-i ,4-benzodiazepin-2- (Example 8-F) one 8C-279 3-(N 3-(Trifluoromethyl)butyric 3-(L-alaninyl)amino-5-(2- C-E 481.1 (Trifluoromethyl)butyryl)-L- acid thienyl)-2 ,3-dihydro- 1-methylalaninyl)amino-5-(2-thienyl)-2 (Fluorochem) 1 H-i ,4-benzodiazepin-2-one dihydro- 1-methyl-i H-i (Example C-Al) benzod iazepin-2-one 8C-280 3-(Trifluoromethyl)butyric 3-(L-alaninyl)amino-5- C-E 481.2 (Trifluoromethyl)butyryl)-L- acid cyclohexyl-2, 3-dihydro alaninyl)amino-5-cyclohexyl-2 (Fluorochem) methyl-i H-i ,4-benzodiazepin-2dihydro-i-methyl-1H-i one benzodiazepin-2-one (Example 8-G) 8C-281i 3-(N 3-(Trifluoromethyl)butyric 3-(L-alaninyl)amino-7-bromo-5- C-E 573.1 (Trifluoromethyl)butyryl)-L- acid (2-fluorophenyl)-2 ,3-dihydro- 1- 574.1 alaninyl)amino-7-bromo-5-(2- (Fluorochem) methyl-i H-i ,4-benzodiazepin-2fluorophenyl)-2 ,3-dihydro- 1- one methyl-i H-i ,4-benzodiazepin-2- (Example 8-D) one__ Example Compound Starting Material I Starting Material 2 General MS No. Procedure 8C-282 N' 3-(Trifluoromethyl)butyric 3-(L-alaninyl)-amino-)2 C-E 541.3 (Trifluoromethyl)butyryl)-L- acid dioxo- 1, 5-bis-(2 ,2alaninyl)-amino-)2 ,4-dioxo- 1,5- (Fluorochem) dimethylpropyl)-2, 3,4,5 bis-(2 ,2-dimethylpropyl)-2 ,3 tetrahydro-1H-1 tetrahydro-1H-1 benzod jazepine _______benzodiazepine 8-V) 8C-283 ,4-Trifluorobutyryl)-L- 4 ,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-2 C -E 557.2 alaninyl)amino-2 ,3-dihydro-5- (Fluorochem) dihydro-5-phenyl- 1 phenyl- 1 ,4-trifluorobutyl)- trifluorobutyl)- 1 H-i ,4- 1 H-i ,4-benzodiazepin-2-one benzodiazepin-2-one ~~(Example 8C-284 -(4,4,4-Trifluorobutyryl)-L- 4 ,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino- 1-(2-oxo-2- C-E 565.2 alaninyl)amino- 1-(2-oxo-2- (Pluorochem) phenylethyl)-2 phenylethyl)-2 ,3-dihydro-5- phenyl- 1H-i ,4-benzodiazepin-2phenyl- lH-1 ,4-benzodiazepin-2- one one (Example 8C-285 ,4-Trifluorobutyryl)-L- 4,4 ,4-Trifluorobutyric acid 3-(L-alaninyl)amino- 1-methyl- C-E 468.1 alaninyl)amino-l1-methyl-2 (Fluorochem) 2, 3-dihydro-5-(2-thiazolyl)- 1Hdihydro-5-(2-thiazolyl)- 1H- 1,4- 1 ,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AH) 8C-286 ,4-Trifluorobutyryl)-L- 4,4 ,4-Trifluorobutyric acid 3-(L-alaninyl)amino-7-chloro- C-E 495.1 alaninyl)amino-7-chloro-2 (Fluorochem) 2, 3-dihydro-l1-methyl-5-phenyl- 1H- 1 H-i ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one (Example 8-C) Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-287 3-(N ,4-Trifluorobutyryl)-L- 4,4 ,4-Trifluorobutyric acid 3-(L-alaninyl)amino-7-chloro-5- C-E 529.1 alaninyl)amino-7-chloro-5-(2- (Fluorochem) (2-chlorophenyl)-2,3-dihydro-i- 531.1 chlorophenyl)-2 ,3-dihydro- 1- methyl-i H-i ,4-benzodiazepin-2methyl-I H-i ,4-benzod iazepin-2- one one 8-F) 8C-288 ,4-Trifluorobutyryl)-L- 4,4 ,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5-(2- C-E 467.1 alaninyl)amino-5-(2-thienyl)-2 (Fluorochem) thienyl)-2 ,3-dihydro- 1-methyldihydro-1-methyl-IH- 1,4- 1 H-i ,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-Al) 8C-289 3 ,4-Trifluorobutyryl)-L- 4,4 ,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5- C-E 467.2 alaninyl)amino-5-cyclohexyl-2, 3- (Fluorochem) cyclohexyl-2, 3-dihydro- 1dihydro- i-methyl-i H-i methyl-i H-i ,4-benzodiazepin-2benzod iazepin-2-one one 8C-290 3-(N ,4,4-Trifluorobutyryl)-L- 4,4 ,4-Trifluorobutyric acid 3-(L-alaninyl)amino-7-bromo-5- C-E 559.1 (Fluorochem) (2-fluorophenyl)-2 ,3-dihydro- 1 560.1 fluorophenyl)-2,3-dihydro-1 methyl- I H-i ,4-benzodiazepin-2methyl-i H-i ,4-benzodiazepin-2- one I_ one (Example Example Compound Starting Material 1 Starting Material 2 General MS No. __________Procedure 8C-29 1 N' -(4,4,4-Trifluorobutyryl)- 4,4 ,4-Trifluorobutyric acid 3-(L-alaninyl)-amino-)-2 C-E 527.3 L-alaninyl)-amino-)-2 ,4-dioxo- (Fluorochem) dioxo- 1,5-bis-(2 ,2- 1 ,5-bis-(2,2-dimethylpropyl)- dimethylpropyl)-2,3 2,3,4,5-tetrahydro-1H-1 tetrahydro-1H-1 benzodiazepine benzodiazepine 8-V) 8C-292 3-(N '-(lsovaleryl)-L- Isovaleric acid 3-(L-alaninyl)amino-2 C-E 517.2 alaninyl)amino-2,3-dihydro-5- (Aldrich) dihydro-5-phenyl-l-(4,4,4phenyl-1 -(4,4,4-trifluorobutyl)- trifluorobutyl)-1H-1 ,4- 1 H-i ,4-benzodiazepin-2-one benzodiazepin-2-one 8C-293 3-('-(Isovaleryl)-L- Isovaleric acid 3-(L-alaninyl)amino-l1-(2-oxo-2- C-E 525.3 alaninyl)amino- 1-(2-oxo-2- (Aldrich) phenylethyl)-2, 3-dihydro-5phenylethyl)-2 ,3-dihydro-5- phenyl- 1H-i ,4-benzodiazepin-2phenyl-1 H-i ,4-benzodiazepin-2- one C-AB) 8C-294 3-(N '-(Isovaleryl)-L- Isovaleric acid 3-(L-alaninyl)amino- 1-methyl- C-E 428.2 alaninyl)amino- 1-methyl-2,3- (Aldrich) 2,3-dihydro-5-(2-thiazolyl)- 1Hdihydro-5-(2-thiazolyl)-1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8C-295 3-(N'-(lsovaleryl)-L- Isovaleric acid 3-(L-alaninyl)amino-7-chloro- C-E 455.2 alaninyl)amino-7-chloro-2 (Aldrich) 2, 3-dihydro-l1-methyl-5-phenyl 1H- 1H- 1,4-benzodiazepin-2-one 1 ,4-benzodik~epin-2-one 8-C) 00 4D Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-296 3-(N'-(Isovaleryl)-L- Isovaleric acid 3-(L-alaninyl)amino-7-chloro-5- C-E 489.1 alaninyl)amino-7-chloro-5-(2- (Aldrich) (2-chlorophenyl)-2 ,3-dihydro- 1- 491.1 chlorophenyl)-2 ,3-dihydro- 1 methyl- I H-i ,4-benzodiazepin-2methyl- 1 H-i ,4-benzodiazepin-2- one one 8-F) 8C-297 3-(N'-(Isovaleryl)-L- Isovaleric acid 3-(L-alaninyl)amino-5-(2- C-E 427.1 alaniny I)amino-5-(2-thienyl)-2 (Aldrich) thienyl)-2 ,3-dihydro- i-methyldihydro-i-methyl-iH-i i H-i ,4-benzod iazepin-2-one benzodiazepin-2-one C-Al) 8C-298 3-(N'-(isovaleryl)-L- Isovaleric acid 3-(L-alaninyl)amino-5- C-F 427.2 alaninyl)amino-5-cyclohexyl-2 (Aldrich) cyclohexyl-2,3-dihydro-i dihydro-i-methyl-IH-i methyl-i H-i ,4-benzodiazepin-2benzod iazepin-2-one one 8-G) 8C-299 3-(N t -(Isovaleryl)-L- Isovaleric acid 3-(L-alaninyl)amino-7-bromo-5- C-E 519.1 alaninyl)amino-7-bromo-5-(2- (Aldrich) (2-fluorophenyl)-2 ,3 -dihydro- 1- 520.1 fluorophenyl)-2 ,3-dihydro- 1- methyl-iH-1 ,4-benzodiazepin-2methyl-i H-i ,4-benzodiazepin-2- one I_ (Example 8-D) Example Compound Starting Material 1 Starting Material 2 General MIS No. Procedure 8C-300 N' -(Isovaleryl)-L-alaninyl)- Isovaleric acid 3-(L-alaninyl)-amino-)-2 C-E 487.3 amino-)-2 ,4-dioxo- 1,5-bis-(2 (Aldrich) dioxo- 1, 5-bis-(2 ,2dimethylpropyl)-2,3 dimethylpropyl)-2,3 tetrahydro- 1H-i tetrahydro-1H-1 benzod iazepine benzod jazepine 8C-30 1 -(L-alpha- L-alpha-Hydroxyisocaproic 3 -(L-alaninyl)amino-2, 3- C-E 547.3 Hydroxyisocaproyl)-L- acid dihydro-5-phenyl- 1 alaninyl)amino-2 ,3-dihydro-5- (Aldrich) trifluorobutyl)- 1 H- 1,4phenyl- 1 -(4,4,4-trifluorobutyl)- benzodiazepin-2-one 1 H-i ,4-benzodiazepin-2-one (Example 8C-302 -(L-alpha- L-alpha-Hydroxyisocaproic 3-(L-alaninyl)amino-I1-(2-oxo-2- C-E 555.3 Hydroxyisocaproyl)-L- acid phenylethyl)-2 alaninyl)amino- I -(2-oxo-2- (Aldrich) phenyl- 1H-i ,4-benzodiazepin-2phenylethyl)-2 ,3-dihydro-5- one phenyl-1IH- 1,4-benzodiazepin-2- (Example C-AB) one 8C-303 -(L-alpha- L-alpha-Hydroxy isocaproic 3-(L-alaninyl)amino- 1-methyl- C-E 458.2 Hydroxyisocaproyl)-L- acid 2, 3-dihydro-5-(2-thiazolyl)- 1Halaninyl)amimo- 1-methy 1-2,3- (Aldrich) 1 ,4-benzodiazepin-2-one dihydro-5-(2-thiazolyl)- 1H- 1,4- (Example C-AH) I_ benzodiazepin-2-one Example Compound Starting Material 1 Starting Material 2 General MS No. 8C-304 -(L-alpha- L-alpha-Hydroxy isocaproic 3-(L-alaninyl)amino-7-chloro- C-E 485.2 Hydroxyisocaproyl)-L- acid 2, 3-dihydro-l1-methyl-5-phenylalaninyl)amino-7-chloro-2 (Aldrich) 111-1 ,4-benzodiazepin-2-one 1H- (Example 8-C) 1 ,4-benzodiazepin-2-one 8C-305 3-(N'-(L-alpha- L-alpha-Hydroxyisocaproic 3-(L-alaninyl)amino-7-chloro-5- C-E 519.1 Hydroxyisocaproyl)-L- acid (2-chlorophenyl)-2,3-dihydro-l- 521.1 alaninyl)amino-7-chloro-5-(2- (Aldrich) methyl-i H-i ,4-benzod iazepin-2chlorophenyl)-2,3-dihydro-1 one methyl-i H-i ,4-benzodiazepin-2- (Example 8-F) one 8C-306 3-(N -(L-alpha- L-alpha-Hydroxyisocaproic 3-(L-alaninyl)amino-5-(2- C-E 457.1 Hydroxyisocaproyl)-L- acid thienyl)-2 ,3-dihydro- 1 -methylalaninyl)amino-5-(2-thienyl)-2, 3- (Aldrich) 1 H-i ,4-benzodiazepin-2-one dihydro-i-methyl-1H-1 (Example C-Al) benzodiazepin-2-one 8C-307 3('-(L-alpha- L-alpha-Hydroxyisocaproic 3-(L-alaninyl)amino-5- C-E 457.3 Hydroxyisocaproyl)-L- acid cyclohexyl-2 ,3-dihydro- 1alaninyl)amino-5-cyclohexyl-2 (Aldrich) methyl-i H-i ,4-benzod iazepin-2dihydro-l1-methyl-iH- 1,4- one benzodiazepin-2-one Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-308 3-N-(L-alpha- L-alpha-Hydroxyisocaproic 3-(L-alaninyl)amino-7-bromo-5 C-E 549.1 Hydroxyisocaproyl)-L- acid (2-fluorophenyl)-2 ,3-dihydro- 1- 550.2 alaninyl)amino-7-bromo-5-(2- (Aldrich) methyl-i H-i ,4-benzodiazepin-2fluorophenyl)-2 ,3-dihydro- 1- one methyl-i H-I ,4-benzodiazepin-2- (Example 8-D) one 8C-309 N' -(L-alpha- L-alpha-Hydroxyisocaproic 3-(L-alaninyl)-amino-)-2 C-E 517.3 Hydroxyisocaproyl)-L-alaninyl)- acid dioxo- 1, 5-bis-(2 ,2amino-)-2 ,4-dioxo- 1,5-bis-(2 (Aldrich) dimethylpropyl)-2 ,3,4,5dimethylpropyl)-2,3,4,5- tetrahydro-1H-i tetrahydro-IH-1 benzodiazepine _______benzodiazepine (Example 8-V) 8C-3 10 L-(+)-Mandelic acid 3-(L-alaninyl)amino-2,3- C-E 567.2 alaninyl)amino-2 ,3-dihydro-5- (Sigma) dihydro-5-phenyl-l1-(4,4,4phenyl-i -(4,4,4-trifluorobutyl)- trifluorobutyl)-1H-i ,4- LH- 1,4-benzodiazepin-2-one benzodiazepin-2-one 8C-311I L-(+)-Mandelic acid 3-(L-alaninyl)amino- I-(2-oxo-2- C-E 575.2 alaninyl)amino-l1-(2-oxo-2- (Sigma) phenylethyl)-2 phenylethyl)-2 ,3-dihydro-5- phenyl-1H-i ,4-benzodiazepin-2phenyl-1 H-i ,4-benzodiazepin-2- one _____(Example C-AB) Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-312 L-(+)-Mandelic acid 3-(L-alaninyl)amino-i-methyl- C-E 478.1 alaninyl)amino-lI-methyl-2, 3- (Sigma) 2, 3-dihydro-5-(2-thiazolyl)- 1Hdihydro-5-(2-thiazolyl)- 1H- 1,4- 1 ,4-benzodiazepin-2-one _______benzodiazepin-2-one 8C-313 3-(N-(L-(+)-Mandelyl)-L- L-(+)-Mandelic acid 3-(L-alaninyl)amino-7-chloro- C-E 505.2 alaninyl)amino-7-chloro-2 (Sigma) 2, 3-dihydro-l1-methyl-5-phenyl- 1H- 1 H-I ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one (Example 8C-3 14 3-(N +)-Mandelyl)-L- +)-Mandelic acid 3-(L-alaninyl)amino-7-chloro-5- C-E 539.1 alaninyl)amino-7-chloro-5-(2- (Sigma) (2-chlorophenyl)-2 ,3-dihydro- 1- 541.1 chlorophenyl)-2,3-dihydro- 1- methyl- I H-i ,4-benzodiazepin-2methyl- I H-i ,4-benzodiazepin-2- one one (Example 8C-315 L-(+)-Mandelic acid 3-(N'-(L-alaninyl)amino-5-(2- C-E 477.1 alaninyl)amino-5-(2-thienyl)-2 (Sigma) thienyl)-2 ,3-dihydro- i-methyldihydro-1-methyl-1H-1 I H-i ,4-benzod iazep in-2 -one benzodiazepin-2-one (Example C-Al) 8C-316 L-(+)-Mandelic acid 3-(L-alaninyl)amino-5- C-E 477.2 alaninyl)amino-5-cyclohexyl-2 (Sigma) cyclohexyl-2 ,3-dihydro- 1dihydro-1-methyl-1H-1 methyl-i H-i ,4-benzodiazepin-2benzodiazepin-2-one one ____(Example_8-G) I t Example Compo und Starting Material I Starting Material 2 General MS No. 8C-3 17 3-(N +)-Mandelyl)-L- +)-Mandelic acid 3-(L-alaninyl)amino-7-bromo-5- C-E 567.1 alaninyl)amino-7-bromo-5-(2- (Sigma) (2-fluorophenyl)-2 ,3-dihydro- 1- 569.1 fluorophenyl)-2 ,3-dihydro- 1- methyl-i H-i ,4-benzodiazepin-2methyl-i H-i ,4-benzodiazepin-2- one one 8C-3 18 3-(N 5-Difluorophenylacetyl)- 3, 5-Difluorophenylacetic 3-(L-alaninyl)amino-5-phenyl- C-G 585.1 L-alaninyl)amino-5-phenyl-2 acid 2,3-dihydro-l1-(3-fluorobenzyl)dihydro-I1-(3-fluoroben~zyl)- 1H- (Aldrich) 1 H-i ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one C-A) 8C-3 19 ,5-Difluorophenylacetyl)- 3 ,5-Difluorophenylacetic 3-(L-alaninyl)amino-5-phenyl- C-G 567.1 L-alaninyl)amino-5-phenyl-2,3- acid 2,3-dihydro-1-(benzyl)- IH-1,Adihydro-i -(benzyl)- 1H-i (Aldrich) benzodiazepin-2-one benzod iazepin-2-one (Example C-B) 8C-320 ,5-Difluorophenylacetyl)- 3 ,5-Difluorophenylacetic 3-(L-alaninyl)amino-5 phenyl- 11 623.2 L-alaninyl)amino-5-phenyl-2 acid 2 ,3-dihydro-l1-(4-tertdihydro-l1-(4-tert-butylbenzyl)- (Aldrich) butylbenzyl)- 1H- 1,4- 1H-i ,4-benzodiazepin-2-one benzodiazepin-2-one ___(Example 8C-32 1 3-(N 5-Difluorophenylacetyl)- 3 ,5-Difluorophenylacetic 3-(L-alaninyl)amino-5-phenyl- C-G 587.2 L-alaninyl)amino-5-phenyl-2,3- acid 2 ,3-dihydro-l1-(2dihydro-l1-(2-cyciohexylethyl)- (Aldrich) cyclohexylethyl)- 1H- 1,4- 1 H-i ,4-benzodiazepin-2-one benzodiazepin-2-one (Example._C-D) I_ Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-322 3-(N'-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic 3-(L-alaninyl)amino-5-phenyl- C-G 561.2 L-alaninyl)amino-5-phenyl-2 acid 2, 3-dihydro-l1-(3,3dihydro- 3-dimethylbutyl)- (Aldrich) dimethylbutyl)- 1H- 1,4- I H-I ,4-benzodiazepin-2-one benzodiazepin-2-one
C-E)
8C-323 3 ,5-Difluorophenylacetyl)- 3 ,5-Difluorophenylacetic 3-(L-alaninyl)amino-5-phenyl- C-G 625.1 L-alaninyl)amino-5-phenyl-2 acid 2, 3-dihydro-I1-(1dihydro-l~-(1 -methoxycarbonyl- 1- (Aldrich) methoxycarbonyl- 1phenylmethyl)- 1H- 1,4- phenylmethyl)-1H-1 ,4benzodiazepin-2-one benzodiazepin-2-one 8C-324 ,5-Difluorophenylacetyl)- 3 ,5-Difluorophenylacetic 3-(L-alaninyl)amino-5-phenyl- C-G 561.2 L-alaninyl)amino-5-phenyl-2 acid 2 ,3-d ihydro-l1-(2-ethylbutyl)dihydro- 1-(2-ethylbutyl)- 1H- 1,4- (Aldrich) 1 H-i ,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-G) 8C-325 3-(N ,5-Difluorophenylacetyl)- 3 ,5 -Difluoropheny ]acetic 3-(L-alaninyl)amino-5-phenyl- C-G 573.2 L-alaninyl)amino-5-phenyl-2,3- acid 2 ,3-dihydro- 1dihydro- 1-(cyclohexylmethyl)- (Aldrich) (cyclohexylmethyl)-l1H-i ,4- 1 H-i ,4-benzodiazepin-2-one benzodiazepin-2-one 8C-326 ,5-Difluorophenylacetyl)- 3 ,5-Difluorophenylacetic 3-(L-alaninyl)amino-5-phenyl- C-G 581.1 L-alaninyl)amino-5-phenyl-2 acid 2, 3-dihydro-l1-(2-phenylethyl)dihydro-l1-(2-phenylethyl)-l1H- (Aldrich) 1 H-i ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-327 3-(N ,5-Ditluorophenylacetyl)- 3 ,5-Difluorophenylacetic 3-(L-alaninyl)amino-5-phenyl- C-G 595.2 L-alaninyl)amino-5-phenyl-2,3- acid 2 ,3-dihydro- 1-(3-phenylpropyl)dihydro-l1-(3-phenylpropyl)- 1H- (Aldrich) 1 H-i ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one (Example C-J) 8C-328 3-(N ,5-Difluorophenylacetyl)- 3 ,5-Difluorophenylacetic 3-(L-alaninyl)amino-5-phenyl- C-G 650.1 L-alaninyl)amino-5-phenyl-2 acid 2, 3-dihydro-l1-(2-(Ndihydro-l1-(2-(N- (Aldrich) phthal imidyl)ethyl)- 1H- 1,4phthalimidyl)ethyl)-lH-i benzodiazepin-2-one benzodiazepin-2-one (Example 8C-329 ,5-Difluorophenylacetyl)- 3 ,5-Difluorophenylacetic 3-(L-alaninyl)amino-5-phenyl- C-G 643.2 L-alaninyl)amino-5-phenyl-2 acid 2 ,3-dihydro- 1-(2dihydro-l1-(2-biphenylmethyl)- (Aldrich) biphenylmethyl)- 1H- 1,4- 1 H-i ,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-L) 8C-330 ,5-Difluorophenylacetyl)- 3, 5-Difluorophenylacetic 3 -(L-alaninyl)amino-5-phenyl- C-G 561.1 L-alaninyl)amino-5-phenyl-2 acid 2 ,3-dihydro-l1-((2dihydro- (Aldrich) tetrahydrofuranyl)methyl)- 1Htetrahydrofuranyl)methyl)-1 H- I ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one C-M) 8C-33 1 5-Difluorophenylacetyl)- 3, 5-Difluorophenylacetic 3-(L-alaninyl)amino-5-phenyl- C-G 625.1 L-alaninyl)amino-5-phenyl-2 acid 2, 3-dihydro- 1,4dihydro- 1,4- (Aldrich) benzodioxanyl)methyl)-l1H- 1,4benzodioxanyl)methyl)- 1H- 1,4- benzodiazepin-2-one benzodiazepin-2-one Example Compound Starting Material 1 -Starting Material 2 General MS No. 8C-332 ,5-Difluorophenylacetyl)- 3 ,5-D ifluorophenyl acetic 3-(L-alaninyl)amino-5-phenyl- C-G 657.1 L-alaninyl)amino-5-phenyl-2 acid 2, 3-dihydro- 1 dihydro- 1 -(3-(5-chlorobenzo[bI (Aldrich) chlorobenzo[bjthienyl))methyl)thienyl)methyl)- 1H- 1,4- I H-i ,4-benzodiazepin-2-one benzodiazepin-2-one C-0) 8C-333 5-Difluorophenylacetyl)- 3 ,5-Difluorophenylacetic 3-(L-alaninyl)amino-5-phenyl- C-G 575.1 L-alaninyl)amino-5-phenyl-2 ,3 acid 2 ,3-dihydro-l1-(3 ,3-dimethyl-2dihydro-l1-(3, 3-dimethyl-2-oxo- (Aldrich) oxo-propyl)- 1H- 1,4propyl)- 1H-i ,4-benzodiazepin-2- benzodiazepin-2-one (Example 8C-334 3-(N ,5-Difluorophenylacetyl)- 3, 5-Difluorophenylacetic 3 -(L-alaninyl)amino-5-phenyl- C-G 609.1 L-alaninyl)amino-5-phenyl-2,3- acid 2,3-dihydro-1 (Aldrich) benzofurazanylmethyl)-1H-1 ,4benzofurazanylmethyl)- 1H- 1,4- benzodiazepin-2-one benzodiazepin-2-one C-Q) 8C-.335 ,5-Difluorophenylacetyl)- 3 ,5-Difluorophenylacetic 3-(L-alaninyl)amino-5-phenyl- C-G 611.1 L-alaninyl)amino-5-phenyl-2 acid 2, 3-dihydro-l1-(3dihydro-I1-(3-phenoxypropyl)- 1H- (Aldrich) phenoxypropyl)- 1H- 1,4- 1 ,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-R) Example Compound Starting Material 1 Starting Material 2 General MIS No. Procedure 8C-336 ,5-Difluorophenylacetyl)- 3, 5-Difluorophenylacetic 3-(L-alaninyl)amino-5-phenyl- C-G 686.1 L-alaninyl)amino-5-phenyl-2, 3- acid 2, 3-dihydro- dihydro- (Aldrich) trifluoromethylquinolinyl)methy trifluoromethylquinolinyl)methyl 1)-i H-i ,4-benzodiazepin-2-one 1H-i ,4-benzodiazepin-2-one (Example C-S) 8C-337 3-(N ,5-Difluorophenylacetyl)- 3 ,5-Difluorophenylacetic 3-(L-alaninyl)amino-5-phenyl- C-G 547.2 L-alaninyl)amino-5-phenyl-2, 3- acid 2, 3-dihydro- I-(2-methylbutyl)dihydro-l1-(2-methylbutyl)- 1H- (Aldrich) 1 H-i ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one 8C-338 ,5-Difluorophenylacetyl)- 3 ,5-Difluorophenylacetic 3-(L-alaninyl)amino-5-phenyl- C-G 505.1 L-alaninyl)amino-5-phenyl-2 acid 2, 3-dihydro- 1 -(ethyl)- 1 H- 1,4d ihydro- 1 -(ethyl)- 1 H- 1,4- (Aldrich) benzodiazepin-2-one benzodiazepin-2-one
C-U)
8C-339 3-(N 5-Difluorophenylacetyl)- 3 ,5-Difluorophenylacetic 3-(L-alaninyl)amino-5-phenyl- C-1 568.1 L-alaninyl)amino-5-phenyl-2,3- acid 2, 3-dihydro-l1-(3dihydro-l1-(3-pyridylmethyl)- 1H- (Aldrich) pyridylmethyl)- 1H- 1,4- 1 ,4-benzodiazepin-2-one benzodiazepin-2-one _____(Example 8C-340 -Difluorophenylacetyl)- 3,5 -Difluorophenylacetic 3-(L-alaninyl)amino-5-phenyl- C-G 676.2 L-alaninyl)amino-5-phenyl-2 acid 2, 3-d ihydro-l1-(2-oxo-2-(Ndihydro-l1-(2-oxo-2-(N- (Aldrich) indolinyl)ethyl)- 1H- 1,4indolinyl)ethyl)-1H-1 benzodiazepin-2-one benzodiazepin-2-one (Example C-W) Example Compound Starting Material 1 Starting Material 2 General MS No. _Procedure 8C-34 1 ,5-D ifluorophenylacetyl)- 3 ,5-Difluorophenylacetic 3-(L-alaninyl)amino-5-phenyl- C-G 586.1 L-alaninyl)amino-5-phenyl-2 acid 2, 3-dihydro-I1-((4-(3 dihydro-l1-(4-(3 (Aldrich) dimethyl)isoxazolyl)methyl)-l1Hdimethyl isoxazolyl)methyl)- 1H- 1 ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one (Example C-Y) 8C-342 ,5-Difluorophenylacetyl)- 3 ,5-Difluorophenylacetic L-alaninyl)amino-5-phenyl-2 acid 2, 3-dihydro-l1-(2-methoxyethyl)dihydro- 1-(2-methoxyethyl)- 1H- (Aldrich) 1 H-i ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one C-Z) 8C-343 -(Cyclopentylacetyl)-L- Cyclopentylacetic acid 3-(L-alaninyl)amino-5-phenyl- C-G 523.2 alaninyl)amino-5-phenyl-2 (Aldrich) 2, 3-dihydro-I1-(benzyl)- 1H- 1,4dihydro-1-(benzyl)-1H-1 benzod iazepin-2-one benzodiazepin-2-one (Example C-B) 8C-344 -(Cyclopentylacetyl)-L- Cyclopentylacetic acid 3-(L-alaninyl)amino-5-phenyl- C-G 579.2 alaninyl)amino-5-phenyl-2 (Aldrich) 2, 3-dihydro-l1-(4-tertdihydro- 1 -(4-tert-butylbenzyl)- butylbenzyl)-1H-1 ,4- I H-i ,4-benzod iazepin-2-one benzodiazepin-2-one _____(Example C-C) 8C-345 3-(N -(Cyclopentylacetyl)-L- Cyclopentylacetic acid 3-(L-alaninyl)amino-5-phenyl- C-G 543.2 alaninyl)amino-5-phenyl-2 (Aldrich) 2,3-dihydro-1-(2dihydro-l1-(2-cyclohexylethyl)- cyclohexylethyl)- 1H-1 ,4- 1 H-i ,4-benzodiazepin-2-one benzodiazepin-2-one ___(ExampleC-D) Example Compound Starting Material 1 Starting Material 2 General MS No. 8C-346 -(Cyclopentylacetyl)-L- Cyclopentylacetic acid 3-(L-alaninyl)amino-5-phenyl- C-C 517.2 alaninyl)amino-5-phenyl-2, 3- (Aldrich) 2, 3-dihydro-l1-(3,3dihydro- 1 ,3-dimethylbutyl)- dimethylbutyl)-1.H-1 ,4- IH-1 ,4-benzodiazepin-2-one benzod iazepin-2-one
C-E)
8C-347 3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic acid .3-(L-alaninyl)amino-5-phenyl- C-G 475.2 alaninyl)amino-5-phenyl-2 (Aldrich) 2, 3-dihydro- 1-(isopropyl)- 1Hdihydro- 1-(isopropyl)-1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one 8C-348 3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic acid 3-(L-alaninyl)amino-5-phenyl- C-G 581.2 alaninyl)amino-5-phenyl-2 (Aldrich) 2 ,3-dihydro-l1-(1dihydro-1-(1-methoxycarbonyl-1 methoxycarbonyl- 1phenylmethyl)-1H-1 phenylmethyl)- 1H-i ,4benzodiazepin-2-one benzodiazepin-2-one
C-F)
8C-349 3 -(Cyclopenty lacetyl)-L- Cyclopentylacetic acid 3-(L-alaninyl)amino-5-phenyl- C-C 517.2 alaninyl)amino-5-phenyl-2 (Aldrich) 2 ,3-dihydro-l1-(2-ethylbutyl)dihydro-1-(2-ethylbutyl)-1H-1 1 H-i ,4-benzodiazepin-2-one benzodiazepin-2-one C-C) 8C-350 -(Cyclopentylacetyl)-L- Cyclopentylacetic acid 3-(L-alaninyl)amin6-5-phenyl- C-G 529.2 alaninyl)amino-5-phenyl-2 (Aldrich) 2,3-dihydro- 1-( dihydro- 1 -(cyclohexylmethyl)- cyclohexylmethyl)- 1 H-i 1,4- 1 H-i ,4-benzodiazepin-2-one benzodiazepin-2-one (ExampleC-H) Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-35 1 3-(N '-(Cyclopentylacetyl)-L- CyclopentylIacetic acid 3-(L-alaninyl)amino-5-phenyl- C-G 537.2 alaninyl)amino-5-phenyl-2, 3- (Aldrich) 2,3-dihydro-l1-(2-pheny lethyl)dihydro-l1-(2-phenylethyl)- 1H- 1 H-i ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one C-I) 8C-352 -(Cyclopentylacetyl)-L- CyclopentylIacetic acid 3-(L-alaninyl)amino-5-pheny[- C-G 551.2 alaniny l)amino-5-phenyl-2 (Aldrich) 2,3-dihydro-lI-(3-phenyipropyl)dihydro-l1-(3-phenylpropyl)- IH- 1 H-i ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one C-J) 8C-353 3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic acid 3-(L-alaninyl)amino-5-phenyl- C-G 606.2 alaninyl)amino-5-phenyl-2 (Aldrich) 2, 3-dihydro-l1-(2-(Ndihydro-l1-(2-(N- phthalimidyl)ethyl)-1H-1 ,4phthalimidyl)ethyl)-IH-1 benzodiazepin-2-one benzodiazepin-2-one (Example C-K) 8C-354 -(Cyclopentylacetyl)-L- Cyclopentylacetic acid 3-(L-alaninyl)amino-5-phenyl- C-G 599.2 alaninyl)amino-5-phenyl-2 (Aldrich) 2, 3-dihydro-l1-(2dihydro-l1-(2-biphenylmethyl)- biphenylmethyl)-1H-1 ,4- 1 H-i ,4-benzodiazepin-2-one benzodiazepin-2-one ___(ExampleC-L) 8C-355 3-(N '-(Cyclopentylacetyl)-L- Cyclopentylacetic acid 3-(L-alaninyl)amino-5 -phenyl- C-G 613.1 alaninyl)amino-5-phenyl-2,3- (Aldrich) 2,3-dihydro-1 dihydro-l1-(3-(5-chlorobenzo[b] chlorobenzollb]thienyl)methyl)thienyl)methyl)- IH- 1,4- 1 H-i ,4-benzodiazepin-2-one benzodiazepin-2-one C-0)I Example Compound Starting Material 1 Starting Material 2 General IMS No. Procedure 8C-356 -(Cyclopentylacetyl)-L- Cyclopentylacetic acid 3-(L-alaninyll)amino-5-phenyl- C-G 531.2 alaninyl)amino-5-phenyl-2 (Aldrich) 2, 3-dihydro-l1-(3, 3-dimethyl-2dihydro-l1-(3 ,3-dimethyl-2-oxo- oxo-butyl)- 1H-1,4butyl)- 1H-1 ,4-benzodiazepin-2- benzodiazepin-2-one one (Example C-P) 8C-357 -(Cyclopentylacetyl)-L- Cyclopentylacetic acid 3-(L-alaninyl)amino-5-phenyl- C-G 565.2 alaninyl)amino-5-phenyl-2 (Aldrich) 2,3-dihydro- dihydro- benzofurazanylmethyl)-1H-1 ,4benzofurazanylmethyl)- 1H- 1,4- benzodiazepin-2-one benzod iazepin-2-one C-Q) 8C-358 3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic acid 3-(L-alaninyl)amino-5-phenyl- C-G 567.2 alaninyl)amino-5-phenyl-2 (Aldrich) 2, 3-dihydro-l1-(3d ihydro-l1-(3-phenoxypropyl)- 1H- phenoxypropyl)- 1H-i ,4- 1 ,4-benzodiazepin-2-one benzodiazepin-2-one
C-R)
8C-359 -(Cyclopenty lacetyl)-L- Cyclopentylacetic acid 3-(L-alaninyl)amino-5-phenyl- C-G 642.2 alaninyl)amino-5-phenyl-2 (Aldrich) 2, 3-dihydro-l1-(6-(2dihydro-1 trifluoromethylquinolinyl)methy trifluoromethylquinolinyl)methyl I)-1H- 1,4-benzodiazepin-2-one 1H-i ,4-benzodiazepin-2-one Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-360 3-(N '-(Cyclopentylacetyl)-L- Cyc lopentylIacetic acid 3-(L-alaninyl)amino-5-phenyl- C-G 487.2 alaninyl)amino-5-phenyl-2,3- (Aldrich) 2, 3-dihydro- 1-( dihydro-1 -(cyclopropylmethyl)- cyclopropylmethyl)-1H-1 ,4- 1 H-i ,4-benzodiazepin-2-one benzodiazepin-2-one 8C-36 1 -(Cyclopentylacetyl)-L- Cyclopentylacetic acid 3 -(L-alaninyl)amino-5-phenyl- C-G 503.2 alaninyl)amino-5-phenyl-2 (Aldrich) 2, 3-dihydro-l1-(2-methylbutyl)dihydro-l1-(2-methylbutyl)- 1H- 1 H-i ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one (Example C-T) 8C-362 3-(N'-(Cyclopentylacetyl)-L- Cyclopentyl acetic acid 3-(L-alaninyl)amino-5-phenyl- C-G 461.2 alaninyl)amino-5-phenyl-2,3- (Aldrich) 2, 3-dihydro-1 -(ethyl)- 1 H- 1,4dihydro-1I-(ethyl)- IH- 1,4- benzodiazepin-2-one benzodiazepin-2-one (Example C-U) 8C-363 -(Cyclopentylacetyl)-L- Cyclopentylacetic acid 3 -(L-alaninyl)amino-5-phenyl- C-G 542.2 alaninyl)amino-5-phenyl-2 (Aldrich) 2,3-dihydro-l1-(4-(3 dihydro-1-(4-(3,5- dimethylisoxazolyl)methyl)- 1Hdiniethylisoxazolyl)inetliyl)- 1H- I ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one (Example C-Y) 8C-364 3-(N'-(Cyclopentylacetyl)-L- Cyclopentylacetic acid 3-(L-alaninyl)amino-5-phenyl- C-G 475.2 alaninyl)amino-5-phenyl-2,3- (Aldrich) 2,3-dihydro-lI-(propyl)-1 H- 1,4dihydro-1-(propyl)-1H-1 benzodiazepin-2-one benzodiazepin-2-one Example Compound Starting Material I Starting Material 2 General MS No. Procedure 8C-365 3 -(Cyclopentylacety Cyclopentylfacet ic acid 3-(L-alaniny l)amino-5-phenyl- C-G 491.2 alaninyl)amino-5-phenyl-2 (Aldrich) 2, 3-dihydro-l1-(methoxyethyl)dihydro-l1-(2-methoxyethyl)- 1H- 1 H-i ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one C-Z) 8C-366 -(4,4,4-Trifluorobutyryl)-L- 4,4,4-Tritluorobutyric acid 3-(L-alaninyl)amino-5-phenyl- C-G 537.1 alaninyl)amino-5-phenyl-2 (Fluorochem) 2,3-dihydro-1 -(benzyl)- LH- 1,4dihydro-1-(benzyl)-1H-1 benzodiazepin-2-one benzodiazepin-2-one (Example 8C-367 ,4-Trifluorobutyryl)-L- 4 ,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5-pheny 1- C-G 593.2 alaninyl)amino-5-phenyl-2 (Fluorochem) 2, 3-dihydro- 1-(4-tertdihydro- 1 -(4-tert-butylbenzyl)- butylbenzyl)-1H-1 ,4- I1H- 1,4-benzod iazepin-2-one benzodiazepin-2-one
C-C)
8C-368 3-(N'-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5-phenyl- C-G 557.2 alaninyl)amino-5-phenyl-2 (Fluorochem) 2, 3-dihydro- 1-(2dihydro- 1 -(2-cyclohexylethyl)- cyclohexylethyl)-1IH- 1,4- 1 H- 1,4-benzodiazepin-2-one benzod iazepin-2-one 8C-369 ,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5-phenyl- C-G 531.2 alaninyl)amino-5-phenyl-2,3- (Fluorochem) 2, 3-dihydro-l1-(3,3dihydro-1-(3 ,3-dimethylbutyl)- dimethylbutyl)-1H-1 ,4- 1 H-i ,4-benzodiazepin-2-one benzodiazepin-2-one Example Compound Starting Material 1 Starting Material 2 General MIS No. _________Procedure 8C-370 3-(N '-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5-phenyl- C-G 489.1 alaninyl)amino-5-phenyl-2 (Fluorochem) 2, 3-dihydro-l1-(isopropyl)- 1Hdihydro-1-(isopropyl)-lH-1 1 ,4-benzodiazepin-2-one benzod iazepin-2-one (Example 8-L) 8C-37 1 ,4,4-Trifluorobutyryl)-L- 4 ,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5-phenyl- C-G 595.1 alaninyl)amino-5-phenyl-2,3- (Fluorochem) 2 ,3-dihydro-l1-(1dihydro-l1-(1 -methoxycarbonyl- 1- methoxycarbonyl- 1phenylmethyl)-1H-1 phenylmethyl)-1H-1 ,4benzod iazepin-2-one benzodiazepin-2-one ____(Example C-F) 8C-372 ,4-Trifluorobutyryl)-L- 4 ,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5-phenyl- C-G 531.2 alaninyl)amino-5-phenyl-2,3- (Fluorochem) 2 ,3-dihydro-l1-(2-ethylbutyl)dihydro-1-(2-ethylbutyl)-1H-1 1H-1 ,4-benzodiazepin-2-one benzodiazepin-2-one C-G) 8C-373 3-(N ,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5-phenyl- C-G 543.2 aianinyl)amino-5-phenyl-2 (Fluorochem) 2,3-dihydro-l1-( dihydro- 1 -(cyclohexylmethyl)- cyclohexylmethyl)-1H-1 ,4- 1 H-i ,4-benzodiazepin-2-one benzodiazepin-2-one ___(Example C-H) 8C-374 3-(N'-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5-phenyi- C-G 565.1 alaninyl)amino-5-phenyl-2 (Fluorochem) 2, 3-dihydro-l1-(3-phenylpropyl)dihydro-l1-(3-phenyipropyl)- 1H- I H-i ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one aExample Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-375 3-(N ,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5-phenyl- C-G 613.2 alaninyl)amino-5-phenyl-2 (Fluorochem) 2, 3-dihydro- 1-(2dihydro-l1-(2-biphenylmethyl)- biphenylmethyl)- 1H- 1,4- IH- 1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-L) 8C-376 3-(N'-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5-phenyl- C-G 627.1 alaninyl)amino-5-phenyl-2 (Fluorochem) 2,3 -dihydro-l1-(3-(5-.
dihydro-l1-(3-(5-chlorobenzo[b] chlorobenzo[blthienyl)methyl)thienyl)methyl)-1H-1 I H-I ,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-0) 8C-377 3 ,4,4-Trifluorobutyryl)-L- 4,4 ,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5 -phenyl- C-G 545.2 alaninyl)amino-5-phenyl-2 (Fluorochem) 2,3-dihydro- 1 ,3-dimethyl-2dihydro- 1 ,3-dimethyl-2-oxo- oxo-butyl)-IH-1 ,4butyl)-1IH- 1,4-benzodiazepin-2- benzodiazepin-2-one one 8C-378 3-(N ,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid 3-(L-alaninyl)amnino-5-phenyl- C-G 579. 1 alaninyl)amino-5-phenyl-2,3- (Fluorochem) 2 ,3-dihydro-1I-(5dihydro- benzofurazanylmethyl)- 1 H-i ,4benzofurazanylmethyl)-1 H-i 1,4- benzodiazepin-2-one benzodiazepin-2-one C-Q) Example Compound Starting Material I Starting Material 2 General MS No. Procedure 8C-379 3-(N'-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5-phenyl- C-G 581.1 alaninyl)amino-5-phenyl-2, 3- (Fluorochem) 2, 3-dihydro-l1-(3dihydro-1-(3-phenoxypropyl)-1 H- phenoxypropyl)- IH-I ,4- 1 ,4-benzodiazepin-2-one benzodiazepin-2-one C-R) 8C-380 ,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5-phenyl- C-G 656.1 alaninyl)amino-5-phenyl-2 (Fluorochem) 2, 3-dihydro-I1-(6-(2dihydro- trifluoromethyiquinol inyl)methy trifluoromethylquinolinyl)methyl l)-IH-1 ,4-benzodiazepin-2-one 1H-i ,4-benzodiazepin-2-one 8C-381 3-(N'-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5-phenyl- C-G 501.1 alaninyl)amino-5-phenyl-2, 3- (Fluorochem) 2, 3-dihydro-l1-( dihydro-l1-(cyclopropylmethyl)- cyclopropylmethyl)-1H-1 ,4- I H-i ,4-benzod iazepin-2-one benzodiazepin-2-one 8-L) 8C-382 3-(N ,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5-phenyl- C-G 517.2 alaninyl)amino-5-phenyl-2 (Fluorochem) 2,3-dihydro-l1-(2-methylbutyl)dihydro-l1-(2-methylbutyl)- IH- 1H-1 ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one 8C-383 3-(N'-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5-phenyl- C-G 475.1 alaninyl)amino-5-phenyl-2,3- (Fluorochem) 2,3-dihydro- 1 -(ethyl)- I H-i ,4dihydro-1I-(ethyl)- IH- 1,4- benzodiazepin-2-one benzodiazepin-2-one Example Compound Starting Material 1 Starting Material 2 General MIS No. Procedure 8C-384 3-(N'-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5-phenyl'- C-G 556.1 alaninyl)amino-5-phenyl-2 (Fluorochem) 2, 3-dihydro- 1 dihydro-l1-(4-(3 dimethyl isoxazolyl)methyl)- I1Hd irnethyl isoxazolyl)methyl)- 1 H- 1 ,4-benzodiazepin-2-one I,4-benzodiazepin-2-one (Example C-Y) 8C-385 ,4-Trifluorobutyryl)-L- 4,4 ,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5-phenyl- C-G 489. 1 alaninyl)amino-5-phenyl-2,3- (Fluorochem) 2 ,3-dihydro-1 -(propyl)- IH- 1,4dihydro-1-(propyl)-1H-1 benzod iazepin-2-one benzodiazepin-2-one 8-L) 8C-386 ,4-Trifluorobutyryl)-L- 4 ,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5-phenyl- C-G 505.1 alaninyl)amino-5-phenyl-2 (Fluorochem) 2, 3-dihydro- 1 -(2-methoxyethyl)d ihydro- 1 -(2-methoxyethyl)- 1 H- 1 H-I ,4-benzodiazepin-2-one 1 ,4-benzodiazepin-2-one 8C-387 34( N'-(L-(+)-Mandelyl)-L- L-(+)-Mandelic acid 3-(L-alaninyl)-amino-)-2,4- C-E 537.3 alaninyl)-amino-)-2,4-dioxo- 1,5- (Sigma) dioxo- 1,5-bis-(2,2bis-(2 ,2-dimethylpropyl)-2,3 dimethylpropyl)-2,3 tetrahydro-1H-1 tetrahydro-1H-1 benzod iazepine benzodiazepine (Example_8-L) 8C-388 N' -(N-pyrrol idinylacetyl)- Pyrrolidine N '-(chloroacetyl)-L- C-F L-alaninyl)amino-2,3-dihydro- 1- (Aldrich) alaninyl)amino-2,3-dihydro- I1methyl-5-phenyl-1H-1 methyl-5-phenyl-1IH-1 ,4benzodiazepin-2-one benzod iazepin-2-one ~~(Example Example Compound Starting Material 1 Starting Material 2 General MS No. 8C-389 3-(N'-(o-Chlorophenoxyacetyl)- o-Chlorophenoxyacetic acid 3-(L-alaninyl)amino-2,3- C-A 504.8 L-alaninyl)amino-2 ,3-dihydro- 1 (Lancaster) dihydro- 1 -methyl-5-phenyl- 1 Hmethyl-5-phenyl-1IH- 1,4- 1 ,4-benzodiazepin-2-one _______benzodiazepin-2-one 8-B) 8C-390 -(2-Thiopheneacetyl)-L- 2-Thiopheneacetic acid 3-(L-alaninyl)amino-2 C-A 460.8 alaninyl)amino-2,3-dihydro-1 (Aldrich) dihydro-l1-methyl-5-phenyl- 1H- -1H-1 1 ,4-benzodiazepin-2-one benzod iazepin-2-one (Example 8-B) 8C-391 3- 3-(L-alaninyl)amino-2,3- C-A 523.1 (Trifluoromethyl)phenyl acetic)- (Trifluoromethyl)phenylacet dihydro-l1-methyl-S -phenyl-l1H- L-alaninyl)amino-2,3-dihydro-1- ic acid 1 ,4-benzodiazepin-2-one -1H-1,4- (Marshailton) (Example 8-B3) benzodiazepin-2-one______________ 8C-392 3-(N'-(p-Tolylacetyl)-L- p-Tolylacetic acid 3-(L-alaninyl)amino-2, 3- C-A 468.8 alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro- 1-methyl-5-phenyl- 1H- -1H-1,4- 1 ,4-benzod iazep in-2 -one benzodiazepin-2-one 8-B) 8C-393 3-(L-alaninyl)amino-2,3- C-A 498.8 Methoxyphenyl)propionyl)-L- Methoxyphenyl)propionic dihydro-l1-methyl-5-phenyl- 1Halaninyl)amino-2 ,3-dihydro- 1- acid 1 ,4-benzodiazepin-2-one 1H- 1,4- (Aldrich) (Example 8-B) I_ benzodiazepin-2-one Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-394 3-(N ,5-Difluorophenylacetyl)- 3 ,5-Difluorophenylacetic 3-(L-alaninyl)amino-2 C-A 491.0 L-alaninyl)amino-2 ,3-dihydro- 1- acid dihydro-i1-methyl-5-phenyl- 1H- 1 H- 1,4- (Aldrich) 1 ,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-395 3-(N'-(m-Tolylacetyl)-L- m-Tolylacetic acid 3-(L-alaninyl)amino-2,3- C-A 468.6 alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-phenyl- 1Hmethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one 8-B) 8C-396 3('-(3-Fluorophenylacetyl)-L- 3-Fluorophenylacetic acid 3-(L-alaninyl)amino-2 C-A 472.8 alaninyl)amino-2,3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-phenyl- 1Hmiethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-397 3-(N'-(3-Bromophenylacetyl)-L- 3-Bromophenylacetic acid 3-(L-alaninyl)amino-2 C-A 535.0 alaninyl)amino-2 ,3-dihydro- 1- (Aldrich) dihydro-i1-methyl-5-phenyl- IHmethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-398 3-(N'-(4-Chlorophenoxyacetyl)- 4-Chiorophenoxyacetic acid 3-(L-alaninyl)amino-2,3- C-A 505.0 L-alaninyl)amino-2 ,3-d ihydro- 1- (Grand Island Biological dihydro-l1-methyl-5-phenyl-1 H- 1H-i A- Company) 1 ,4-benzodiazepin-2-one benzodiazepin-2-one 8-B) 8C-399 3-(N '-(2-Naphthylacetyl)-L- 2-Naphthylacetic acid 3-(L-alaninyl)amino-2 C-A 505.0 alaninyl)amino-2, 3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-phenyl- 1Hmethyl-5-phenyl-1H-1 1 ,4-benzodiazepin-2-one _______benzodiazepin-2-one Example Compound Starting Material 1 Starting Material 2 General MS No. 8C-400 -(3-Methyiphenoxyacetyl)- 3-Methyiphenoxyacetic acid 3 -(L-alaninyl)amino-2 C-A 489.0 L-alaninyl)arnino-2 ,3-dihydro- 1- (Lancaster) dihydro-lI-methyl-5-phenyl- IHmethyl-5-phenyl-IH-1 1 ,4-benzodiazepin-2-one benzodiazepin-2-one WO 98/28268 PCT/US97/22986 502 GENERAL PROCEDURE C-J A vial was charged with a CHCI 3 solution of Starting material 1 (71 umol), a DMF solution of HOBt monohydrate (71 umol), a CHC1 3 solution of diisopropylcarbodiimide (71 umol), and a CHCl 3 solution of starting material 2 (60 umol). The vial was capped and the solution allowed to stand at room temperature for two days. The reaction mixture was loaded onto a cation exchange column, washed with MeOH and eluted with 2 N NH 3 /MeOH. The eluents were concentrated and dried to give the desired product as determined by MS (IS) and HPLC.
GENERAL PROCEDURE C-K To a 4 mL vial was added 870 uL of 0.05 mM stock solution of starting material 1 in DMF/chloroform, 1000 uL of a 0.05 mM stock solution of starting material 2 in chloroform, 1000 uL of a 0.05 mM stock solution of 1-(3dimethylaminopropyl)-3-ethyl carbodiimide in chloroform and 100 uL of a 0.48 mM stock solution of HOBt in DMF. After standing undisturbed for 48 h, the reaction mixture was concentrated and the residue redissolved in 2 mL of a methanol/methylene chloride solution. This solution was then filtered through a pre-washed (methanol) 500 mg SCX column using an additional 8 mL of the same solvent. The filtrate was concentrated under a stream of nitrogen to approximately 1/3 its original volume and then passed over a plug (200 mg) of AG 1-8x anion exchange resin (BioRad; Hercules, California; Columns were pre-washed with 1N NaOH, water and methanol) using an additional 6 mL of 10% methanol/methylene chloride solution. The resulting filtrate was concentrated under vacuum and the crude products were submitted for testing without further purification. Product structure and purity were confirmed by HPLC and IEX MS.
Example C-AE Synthesis of 3-[(L-Alaninyl)amino]-2,3-dihydro-l-methyl- 5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one WO 98/28268 PCTIUS97/22986 503 Step A: Synthesis of 3 -Amino- 2 ,3-dihydrol1methyl5(2-pyridyl)- LH-1 ,4-benzodiazepin-2-one The title compound was synthesized as described in Synth. Commun., 26(4), 721-727 (1996).
Step B: Synthesis of 3 -[(N-tert-Butoxycarbonyl-Lalaninyl)aino]- 2,3-dihydro-l-methyl-5-(2-pyridyl)..H-1,4-benzodiazepin- 2-one A solution of L-Boc-alanine (1.74 g, 9.20 mmol), HOBt monohydrate (1.24 g, 9.20 mmol), diisopropylethylamnime (1.6 mL, 9.20 mnmol) and C11 2 C1 2 mL) was purged with nitrogen and cooled in an ice bath. To the cold solution was added 1 3 -dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (1.76 g, 9.20 mmol) followed by a solution of 3-amino-2,3dih ydro-l1-methyl-5-(2-pyridyl)- 1H-i 4 -benzodiazepin-2-one (2.45 g, 9.20 mmol) dissolved in CH2C1 2 (15 mL). The cold bath was removed and the solution stirred overnight at room temperature. The reaction mixture was extracted with H 2 0, 0.1 N aq. citric acid, 5 aq. NaHCO 3 and brine. The remaining CH,CI, solution was dried (MgSO 4 and concentrated to a tan foam.
The title compound was crystallized from CHC1 2 /EtOAc to give 3.47 g (86% yield) of white crystals, mp. 228-229*C.
Anal. Calcd for C' 23
H
27
N
5 0 4 C, 63.14; H, 6.22; N, 16.01. Found: C, 63.25; H, 6.15; N, 15.95. MS 437 mlz.
Step C: Synthesis of 3 -[(L-Mlaninyl)amino]-2,3-clihydro-1-methyl- 5-(2-pyridyl)-1H-1 ,4-benzodiazepin-2-one A solution of 3 -[(N-tert-butoxycarbony-L-alaninyl)amino] 3-dihydro- 1methyl-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one (3.42 g, 7.82 mmol) in
CH
2 C1 2 (90 mL) was cooled in an ice bath and treated with TFA (13.2 mL, 172 mmol). The cold bath was removed and the solution stirred at room temperature for four hours. The reaction mixture was washed with 1 M aq.
K'_C0 3 and the aqueous back-extracted with CH 2 The combined extracts were washed with H,0, dried (MgSO,) and concentrated to obtain 1.75 g (66% yield) of the title compound as an off-white foam. MS 338 WO 98t28268 PTU9/28 PCT/US97/22986 504 -HNMR (CDCl 3 6= 8.76-8.86 (1H1, in), 8.63 (1H1, in), 8.17 (1H, in), 7.82 (2H, mn), 7.60 (1H, in), 7.41 (3H, mn), 5.60 (1H, in), 3.63 (1H, in), 3.49 (3H, 1.66 (211, broad), 1.45 (3H, in).
Example C-AF Synthesis of 3-[(L-Alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl).
5-(2-pyridyl)-1H-1 ,4-benzodiazepin-2-one Step A: Synthesis of 3-Amino-2,3-dihydro-1-(2-N,NdiethylanminoethyI)-5-(2-pyridyl)-lH-1,4-benzodiazepin-2 one The title compound was synthesized as described in Synth. Commun., 26(4), 721-727 (1996).
Step B: Synthesis of 3-[(N-tert-Butoxycarbonyl-L-alaninyl)amino]- 2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2pyridyl).H.
1 ,4-benzodiazepin-2-one A solution of L-Boc-alanine (1.80 g, 9.50 mmol), HOBt inonohydrate (1.28 g, 9.50 inmol), diisopropylethylarne (1.65 mL, 9.50 inmol) and CH 2 Cl 2 (40 inL) was purged with nitrogen and cooled in an ice bath. To the cold solution was added 1 -(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (1.82 g, 9.50 inmol) followed by a solution of 3-amino-2,3dihydro-l1-(2-N, N-diethylaminoethyl)-5-(2-pyridyl)- 1H- 1,4-benzodiazepin-2-one (3.34 g, 9.50 mmol) dissolved in CH- 2 C1 2 (25 inL. The cold bath was removed and the solution stirred overnight at room temperature. The reaction mixture was extracted with H,O, 5 aq. NaHCO 3 and brine. The remaining CH 2 Cl 2 solution was dried (MgSO 4 and concentrated to a tan foam. The title compound was isolated via column chromatography MeOH/CH 2 Cl 2 to MeOH/CH 2
CI
1 to give 3.53 g (71 yield) of yellow foam.
MS 522 'HNMR (CDCI 3 3 8.62 (1H1, 8.11 (1H, in), 7.80 (214, mn), 7.59 (2H, in), 7.32-7.45 (2H1, mn), 5.54 (11H, in), 5.02-5.18 (111. mn), 4.38 (11, in), WO 98/28268PcTU9I98 PCTIUS97t22986 505 4.20 (111, in), 3.83 (1H, in), 2.62 (2H, 2.44 (4H1, in), 1.40-1.56 (12H, in), 0.88 (6H, in).
Step C: Synthesis of 3-[(L-Alaninyl)amino]-2,3-dihydro-l-(2-N,Ndiethylaminoethyl)- 5-(2-pyridyl)-1H-1 ,4-benzodiazepin-2one The title compound was synthesized using the procedure described in Example C-AE, Step C. A solution of 3-[N-tert-butoxycarbonyl-Lalaninyl)amino] -2 ,3-dihydro-l1-(2-N, N-diethylaminoethyl)-5-(2-pyridyl)-l1H- 1,4benzodiazepin-2-one (3.52 g, 6.73 inmol) was treated with TFA (11.4 mL, 148 inmol) to give 2.61 g (92% yield) the title compound as a light yellow foam.
MS 423 'HNMR (CDCl 3 6 8.78-8.93 (11H, in), 8.62 8.11 (1H, in), 7.80 (2H, mn), 7.58 (211, mn), 7.39 (2H1, in), 5.58 (11H, in), 4.22 (111, in), 3.88 (1H1, in), 3.61 (11H, in), 2.67 (2H1, 2.49 (4H, in), 1.73 (2H, broad), 1.42 (3 H, mn), 0. 91 (6H1, m).
Example C-AG Synthesis of 3-[(L-Alaninyl)amino]-2,3-dihydro-1-(3 ,3-dimethyl-2-oxobutyl)- S-(2-pyridyl)-1H-1,4-benzodiazepin-2-one Step A: Synthesis of 3-Amiino-2,3-dihydro-1-(3,3-dimnethyl-2oxobutyl)-5-(2-pyridyl)-1H-1 ,4-benzodiazepin-2-one The title compound was synthesized as described in Synth. Commun., 26(4), 721-727 (1996).
Step B: Synthesis of 3-[(N-tert-Butoxycarbonyl-L-alaninyl) axino]- 2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)- 5-(2-pyridyl)-1H- 1 ,4-benzodiazepin-2-one A solution of L-Boc-alanine (1.57 g, 8.33 inmol), HOBt monohydrate (1.13 g, 8.33 minol), diisopropylethylamiine (1.45 mL, 8.33 iniol) and CHCl 2 inL)was purged with nitrogen and cooled in an ice bath. To the cold solution was added 1 -(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (1.60 g, 8.33 nimol) followed by a solution of 3-amino-2,3- WO 98/28268 PTU9128 PCT[US97/22986 506 dihydro- 1 3-dimethyl-2-oxobutyl)-5-(2-pyridyl)- 1 H- 1,4-benzodiazepin-2-one (2.92 g, 8.33 mmol) dissolved in CH,CI-, (25 mL). The cold bath was removed and the solution stirred overnight at room temperature. The reaction mixture was extracted with H 2 0, 0. 1 N aq. citric acid, 5 aq. NaHCO 3 and brine.
The remaining CH 2
CI
2 solution was dried (NgOW and concentrated to a yellow foam. The title compound was isolated via column chromatography EtOAc/hexanes to 60% EtOAc/hexanes) to give 4.19 g (96% yield) of light yellow-foam.
MS 521 (mlz).
HNMR (CDCI 3 6 8.65 (111, 8.17 (1H, 7.90 (1Hi, 7.71-7.85 (1H, in), 7.54 (111, in), 7.44 (111, 7.37 7.24-7.32 (1H1, in), 7.14 (1H4, mn), 5.67 (1H1, dd), 5.18 (1H, broad), 4.93-5.07 (1H1, in), 4.50-4.64 (1H, in), 4.38 (1H, broad), 1.42-1.51 (12H, in), 1.26 (9H, d).
SteD C: Synthesis of 3-IIL-Alaninyl) amino] -2,3-dihydro- 1-(3,3dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1 ,4-benzodiazepin- 2-one The title compound was synthesized using the procedure described in Example C-AE, Step C. A solution of 3-[(N-tert-butoxycarbonyl-Lalaninyl)ainino]-2 ,3-dihydro-l1-(3, 3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H- 1,4benzodiazepin-2-one (4.18 g, 8.01 mmol) was treated with TFA (13.6 inL, 176 inmol) to give 3.14 g (93% yield) the title compound as an off-white foam.
MS UIS') 422 Wme).
'HNMR (CDC1 3 6 8.85-8.99 (1H1, in), 8.68 (1H, 8.20 (1H, 7.87 (11H, 7.58 (1H, 7.42 2H, in), 7.30 (1H, 7.17 (1H1, 5.72 (1H, in), 5.08 (1H1, 4.60 3.66 (1H1, in), 1.47 (311, in), 1.28 (911, in).
Example C-All Synthesis of 3-[(L-Alaninyl)amino]-2,3-dihvdro-l-methyl- 5-(2-thiazyl)-1H-1 ,4-benzodiazepin-2-one Step A: Synthesis of 3-Amino-2,3-dihydro-1-inethyl-5-(2-thiazyl)- 1H-1 ,4-benzodiazepin-2-one WO 98/28268 PCT/US97/22986 507 The title compound was synthesized in a manner Similar to the procedure described in Synth. Commun., 26(4), 72 1-727 (1996), starting with 2-(2aminobenzoyl)thiazole (prepared as described in Tetrahedron, 51(3), 773-786, (1995)).
MS 273 1HNMR (CDCl 3 6 7.83-7.94 (21-1, in), 7.61 (1H1, 7.50 (11H, 7.34 (2H1, 4.60 (1H1, 3.46 1.97 (211, broad).
Step B: Synthesis of 3 -[(N-tert-Butoxycarbonyl-L-alaninyl)amjno].
2 ,3-dihydro-1-methyl-5-(2-thiazyl)..H-1 ,4-benzodiazepin- 2-one A solution of L-Boc-alanine (1.85 g, 9.77 inmol), HOBt monohydrate (1.32 g, 9.77 inmol), diisopropylethylamime (1.70 mL, 9.77 mmol) and CH 2 Cl 2 mL) was purged with nitrogen and cooled in an ice bath. To the cold solution was added 1 3 -dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (1.87 g, 9.77 inmol) followed by a solution of 3-amino-2,3dihydro-l1-methyl-5-(2-thiazyl)-l1H-i ,4-benzodiazepin-2-one (2.66 g, 9.77 inmol) dissolved in CH 2
CI
2 (20 mL). The cold bath was removed and the solution stirred o vernight at room temperature. The reaction mixture was extracted with H,O, 0.1 N aq. citric acid, 5% aq. NaHCO 3 and brine. The remaining CH.,C1 2 solution was dried NgOW) and concentrated to a light yellow foam.
The title compound was crystallized from EtOAc/hexane to give 3.22 g (74% yield) of white crystals, mp. 196-197C. Anal. Calcd for C 2 jH2N 5
O
4
S:
C, 56.87; H, 5.68; N, 15.79. Found: C, 56.74; H, 5.75; N, 15.55.
MS 444 m/e.
Step C: Synthesis of 3-[(L-Alaninyl)amino]-2,3-dihydro-1-methyl- 5-(2-thiazyl)-1H-1 ,4-benzodiazepin-2-one The title compound was synthesized using the procedure described in Example C-AE, Step C.
WO 98/28268 PCTUS97/22986 508 Example C-Al Synthesis of 3-[(L-Alaninyl)anuino]-2 ,3-dihydro-1-methyl- 5-(thiophen-2-yl)-1H- 1, 4 -benzodiazepin-2-one Step A: Synthesis of 3 -Amino-2,3-dihydro1-methyl5(2-thiophen- 2-yl)-1H-1 ,4-benzodiazepin-2-one The title compound was synthesized in a manner similar to the procedure described in Synth. Commun., 26(4), 72 1-727 (1996), starting with 2-(2aminobenzoyl)thiophene (prepared as described in Collect. Czech. Chem.
Commun., 34(2), 468-478, (1969)).
MS 272 (mle).
'HNMR (CDCl 3 6 7.68 (i11, 7.60 (1H, 7.48 (111, in), 7.35 (2H, 7.28 (i1H, in), 7.15 (i1H, 7.05 (1Hl, 4.50 (i11, broad), 3.45 (3H, 2.26 (2H, broad).
Step B: Synthesis of 3 -[(N-tert-Butoxycarbonyl-L-alaniny)anino].
2 ,3-dihydro-1-methyl-5-(2-thiophenyl)..1H-1,4benzodiazepin-2-one The title compound was synthesized in a manner similar to the procedure described in Example C-All, Step B.
MS 443 'HNMR (CDCI 3 6 7.69 (11H, 7.61 (2H, in), 7.48 (1H, 7.27- 7.42 (2H, mn), 7.18 (1H, in), 7.05 (i1H, in), 5.51 (1H, 5.13 (1H, broad), 4.36 (1H, broad), 3.44 (3H1, 1.38-1.57 (12H, in).
Step C: Synthesis of 3 -[(L-Alaninyl)anino]2,3dihydrolmethyl 5-(2-thiophenyl)-1H-1 4 -benzodiazepin-2-one The title compound was synthesized in a manner similar to the procedure described in Example C-AE, Step C.
MS 343 1 HNMR (CDCI 3 6 8.55 (i1H, 7.68 (i14, 7.59 (i1H, in), 7.48 (i1H, 7.36 (i1H, 7.31 (i111, 7.16 (IH, in), 7.04 (1H. 5.54 (i1H, d), 3.58 (1H, 3.45 (3H, 1.41 (3H, d).
WO 98/28268 PCTIUS97/22986 509 Using the procedures indicated, the compounds shown in Table C-2 were prepared.
Table C-2 Example Compound Starting Material I Starting Material 2 General MS No. 8C-40 1 '-(4-methoxypheny lacety 4-Methoxyphenylacetic 3 -[(L-alani ny ])amino] -2,3 C-J 485.5 alaninyl)aminoj-2 ,3-dihydro- 1- acid dihydro- 1-methyl-5-(2-pyridyl)methyl-5-(2-pyridyl)-1H-1 (Aldrich) 1H-1 ,4-benzodiazepin-2-one _______benzodiazepin-2-one C-AE) 8C-402 '-(2-thiopheneacetyl)-L- 2-Thiopheneacetic acid 3-[L-alaninyl)amino]-2 C-J 461.5 alani nyl])amino] -2,3 -dihydro- 1 (Aldrich) dihydro- 1 -methyl-5-(2-pyridyl)methyl-5-(2-pyridyl)-1IH- 1,4- 1 H-i ,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8C-403 ,5-difluorophenylacetyl)-L- 3 ,5-Ditluorophenylacetic 3-[(L-alaninyl)amino,]-2 C-J 491.5 alaninyl)amino]-2 ,3-dihydro- 1- acid dihydro- 1-methyl-5-(2-pyridyl)methyl-S -(2-pyridyl)- 1H- 1,4- (Aid rich) I H-i ,4-benzodiazepin-2-one benzodiazepin-2-one
C-AE)
8C-404 '-(3-bromophenylacetyl)-L- 3-Bromophenylacetic acid 3-[L-alaninyl)amino]-2 C-J 534.4 alaninyl)aminoJ-2 ,3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-(2-pyridyl)methiyl-5-(2-pyridyl)-1H- 1,4- 111-1 ,4-benzodiazepin-2-one _______benzodiazepin-2-one (Example 8C-405 '-(phenylmercaptoacetyl)-L- Phenylmercaptoacetic acid 3-[(L-alaninyl)aminoJ C-J 487.6 alaninyl)aminol-2,3-dihydro- 1 (Aldrich) dihydro-l1-methyl-5-(2-pyridyl)methyl-5-(2-pyridyl)- 1H- 1,4- 1H-1 ,4-benzodiazepin-2-one _______benzodiazepin-2-one Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-406 '-(4-ethoxyphenylacetyl)-L- 4-Ethoxyphenylacetic acid 3- [L-alaninyl)aminoj-2 C-J 499.6 alaninyl)aminoj-2 ,3-dihydro- 1- (Aldrich) dihydro- 1-methyl-5-(2-pyridyl)methyl-5-(2-pyridyl)-1H-1 1H-1 ,4-benzodiazepin-2-one _______benzodiazepin-2-one 8C-407 4- 3-[(L-alaninyl)amino]-2,3- C-i 523.5 (tri fluoromethy l)phenylacetyl)-L- (trifluoromethyl)phenylacet dihydro- 1-methyl-5-(2-pyridyl)alaninyl)aminol-2 ,3-dihydro- 1- ic acid 1 H-i ,4-benzodiazepin-2-one methyi-5-(2-pyridyl)- 1H- 1,4- (Aldrich) (Example C-AE) ________benzodiazepin-2-one 8C-408 3,5-bis(trifluoromethyl) 3-[L-alaninyl)aminoj-2,3- C-i 591 bis(trifluoromethyl)phenylacetyl)-L- phenylacetic acid dihydro- 1-methyl-5-(2-pyridyl)alaninyl)aminoj-2,3-dihydro-1 (Aldrich) 1 H-i ,4-benzodiazepin-2-one methyl-5-(2-pyridyl)-IH-1 (Example C-AE) I benzodiazepin-2-one 8C-409 3-[N '-((methylthio)acetyl)-L- (methylthio)acetic acid 3-IIL-alaninyl)aminoj-2 C-J 425.5 alaninyl)aminol-2 ,3-dihydro-1 (Aldrich) dihydro-l1-methyl-5-(2-pyridyl)rnethyl-5-(2-pyridyl)-1H-1 1H-1 ,4-benzodiazepin-2-one nzod iazepin-2-one (Example 8C-410 3-(N'-(cyclohexyiacetyl)-L- cyclohexylacetic acid 3-[L-alaninyI)aminoJ-2,3- C-J 461 .6 alaninyl)aminoJ-2 ,3-dihydro- 1- (Aldrich) dihydro- 1 -methyl-5-(2-pyridyl)methyl-5-(2-pyridyl)-1H-1 1 H-i ,4-benzodiazepin-2 -one _______benzodiazepin-2-one C-AE) Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-411I 3-[(N'-(pentafluorophenoxyacetyl)- pentafluorophenoxyacetic 3-IIL-alaninyl)aminol-2,3- C-J 561.5 L-alaninyl)amino]-2,3-dihydro- 1- acid dihydro- I -methyl-5-(2-pyridyl)methyl-5-(2-pyridyl)-1IH- 1,4- (Aldrich) I H- 1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8C-412 3-[(N'-(benzo[bJthiophene-3-acetyl)- benzo thiophene-3- 3-[(L-alaninyl)aminol-2,3- C-I 511.6 L-alaninyl)amino]-2 ,3-dihydro- 1- acetic acid dihydro- I-methyl-5-(2-pyridyl)methyl-5-(2-pyridyl)- 1 H- 1,4- (Lancaster) 1 H-i ,4-benzodiazepin-2-onie benzodiazepin-2-one
C-AE)
8C-4 13 2 ,4,6-trimethylphenyl acetic 3-[(L-alaninyl)amino]-2 C-I 497.6 trimethylphenylacetyl)-L- acid dihydro- 1 -methyl-5-(2-pyridyl)alaninyl)aminol-2 ,3-dihydro- 1- (Lancaster) 1 H-i ,4-benzodiazepin-2-one methyl-5-(2-pyridy 1)-iH-I A- (Example C-AE) benzod iazepin-2-one______ 8C-4 14 3-[(N'-(4-biphenylacetyl)-L- 4-biphenylacetic acid 3-[L-alaninyl)aminoJ-2 C-I 531.6 alaninyl)amino]-2 ,3-dihydro- 1- (Lancaster) dihydro- 1-methyl-5-(2-pyridyl)meth~yl-5-(2-pyridyl)- I-I I H-i ,4-benzodiazepin-2-one benzodiazepin-2-one
C-AE)
8C-4 15 ,4-difluorophenylacetyl)-L- 3 ,4-difluorophenylacetic 3-[(L-alaninyl)amino]-2, 3- C-J 491.5 alaninyl)amino]-2 ,3-diliydro- 1- acid dihydro- I-niethyl-5-(2-pyridyl)metliyl-5-(2-pyridyl)-IH-1 (Aldrich) 1H-1 ,4-benzodiazepin-2-one iazepin-2-one (Example C-AE) Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-4 16 '-(4-(2-thienyl)butyryl)-L- 4-(2-thienyl)butyric acid 3-[(L-alaninyl)aminol-2 C-J 489.6 alaninyl)aminol 3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-(2-pyridyl)methyl-5-(2-pyridyl)-1H-1 1 H-i ,4-benzodiazepin-2-one iazepin-2-one C-AE) 8C-4 17 '-(5-methylhexanoyl)-L- 5-methylhexanoic acid 3-[L-alaninyl)aminol-2 C-J 449.5 alaninyl)amino]-2 ,3-dihydro- 1- dihydro-I1-methyl-5-(2-pyridyl)methyl-5-(2-pyridyl)-1H-1 1 H-i ,4-benzod iazepin-2 -one iazepin-2-one (Example 8C-418 mono-methyl succinate 3-I(L-alaninyl)aminoj-2,3- C-J 451.5 methoxycarbonylpropionyl)-L- (Aldrich) dihydro-l1-methyl-5-(2-pyridyl)alaninyl)amino]-2,3-dihydro-1 1 H-i,4-benzodiazepin-2-one methyl-5-(2-pyridyl)-1H-1 (Example C-AE) benzodiazepin-2-one 8C-4 19 '-(methanesulfonylacetyl)-L- methanesulfonylacetic acid 3-RL-alaninyl)aminol-2 C-J 457.5 alaninyl)amino] 3-dihydro- 1- (Lancaster) dihydro-l1-methyl-5-(2-pyridyl)methyl-5-(2-pyridyl)-I1H-1 1H-1 ,4-benzodiazepin-2-one iazepin-2-one (Example C-AE) 8C-420 3-II(N '-(4-toluenesuifonylacetyl)-L- 4-toluenesulfonylacetic 3-[L-alaninyl)aminol-2,3- C-J 533.6 alaninyl)amino]-2,3-dihydro- 1- acid dihydro-lI-methyl-5-(2-pyridyl)methyl-5-(2-pyridyl)- 1H- 1,4- (Lancaster) 1 H-i ,4-benzodiazepin-2-one benzodiazepin-2-one C-AE) Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-421I 3-(N ,6-dilfluoromandelyl)-L- 2,6-difluoromandelic acid 3-[L-alaninyl)aminol-2, 3- C-J 507.5 alaninyl)aminoJ 3-dihydro- 1- (Fluorochem) dihydro-l1-methyl-5-(2-pyridyl)methyl-5-(2-pyridyl)-lH-1 1 H-i ,4-benzodiazepin-2-one benzodiazepin-2-one 8C-422 3-[N '-(4-tluoromandelyl)-L- 4-fluoromandelic acid 3-[L-alaninyl)amino]-2,3- C-J 489.5 alaninyi)aminol-2 ,3-dihydro- 1- (Lancaster) dihydro- 1 -methyl-5-(2-pyridyl)methyl-5-(2-pyridyl)-I11-l 1,4- 1 H-i ,4-benzodiazepin-2-one _______benzodiazepin-2-one
C-AE)
8C-423 3-[N '-(2,5-difluoromandelyl)-L- 2,5-difluoromanclelic acid 3-IIL-alaninyl)amino]-2 C-J 507.5 alaninyl)aminol-2 ,3-dihydro- 1- (Fluorochem) dihydro-lI-methyl-5-(2-pyridyl)inethyl-5-(2-pyridyl)-1H-i 1 H-i ,4-benzodiazepin-2-one benzod iazepin-2-one (Example C-AE) 8C-424 '-(2,4,6-trifluorophenylacetyl)- 2,4,6-trifluorophenylacetic 3-[(L-alaninyl)amino]-2,3- C-J 509.5 L-alaninyl)amino]-2 ,3-diliydro- 1- acid dihydro- 1-methyl-5-(2-pyridyl)methyl-5-(2-pyridyl)- 1H-i (Fluorochem) 1 H-i ,4-benzodiazepin-2-one benzod iazepin-2-one C-AE) 8C-425 3-[(N'-(4-fluoro-2- 4-fluoro-2- 3-IIL-alaninyl)aminol-2,3- C-J 541.5 (trifluoromethyl)pheny lacety (trifluoromethyl) dihydro-lI-methyl-5-(2-pyridyl)alaninyl)aminol-2, 3-dihydro- 1- phenylacetic acid 1 H-i ,4-benzodiazepin-2-one methyl-5-(2-pyridyl)- 1H- 1,4- (Fluorochem) (Example C-AE) _______benzodiazepin-2-one I Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-426 ,4,4-trifluorobutyryl)-L- 4,4,4-trifluorobutyric acid 3-[L-alaninyl)amino]-2 C-J 461.4 alaninyl)aminoj 3-dihydro- 1- (Fluorochem) dihydro-lI-methyl-5-(2-pyridyl)methyl-5-(2-pyridyl)-1H-1 1 H-i ,4-benzodiazepin-2-one iazepin-2-one C-AE) 8C-427 '-(4-isopropylphenylacetyl)-L- 4-isopropyiphenylacetic 3-[L-alaninyl)amino]-2 C-J 497.6 alaninyl)amino]-2,3-dihydro- 1- acid dihydro-l1-methyl-5-(2-pyridyl)methyl-5-(2-pyridyl)- IH- 1,4- (Lancaster) 1 H-i ,4-benzodiazepin-2-one _______benzodiazepin-2-one C-AE) 8C-428 3-[N '-(beta-phenyllactyl)-L- beta-phenyllactic acid 3-[L-alaninyl)amino]-2 C-J 485.5 alaninyl)amino] 3-dihydro- 1- (Sigma) dihydro- 1-methyl-5-(2-pyridyl)methyl-5-(2-pyridyl)-IH-1 1 H-i ,4-benzodiazepin-2-one benzod iazepin-2-one 8C-429 3-[(N'-(mandelyi)-L- mandelic acid 3-[L-alaninyl)amino]-2,3- C-J 471.5 alaninyl)aminoj-2 ,3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-(2-pyridyl)methyl-5-(2-pyridyl)- 11- 1,4- 1IH- 1,4-benzodiazepin-2-one _______benzodiazepin-2-one (Example C-AE) 8C-430 3-IN'-(4-chloromandelyl)-L- p-chloromandelic acid 3-[L-alaninyl)aminoj-2,3- C-J 506.0 alaninyl)aminol-2 ,3-dihydro- 1- (Acros) dihydro-l1-methyl-5-(2-pyridyl)methyl-5-(2-pyridyl)-11H- 1,4- 1 H-i 1,4-benzod iazepin-2 -one benzodiazepin-2-one
C-AE)
8C-431 3-[(N'-(isovaleryl)-L- isovaleric acid 3-[L-alaninyl)amino]-2,3- C-J 421.5 alaninyl)aminoj-2 ,3-dihydro- 1- (Aldrich) dihydro- 1-methyl-5-(2-pyridyl)methyl-5-(2-pyridyl)-1--1 1H-1 ,4-benzodiazepin-2-one _______benzodiazepin-2-one C-AE) Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-432 ,5-tritluorophenylacetyl)- 2,3 ,5-trifluorophenylacetic 3-[(L-alaninyl)aminol-2,3- C-J 509.5 L-alaninyl)aminol-2 ,3-dihydro- 1- acid dihydro-l1-methyl-5-(2-pyridyl)methyl-5-(2-pyridyl)- 1H- 1,4- (Fluorochem) 1 H-i ,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8C-433 '-(3-methylthiopropionyl)-L- 3 -methylIthiopropionic acid 3-[L-alaninyl)aminol-2,3- C-1 439.5 alaninyl)amino]-2 ,3-dihydro- 1- (Lancaster) dihydro- 1-methyl-5-(2-pyridyl)methyl-5-(2-pyridyl)- 1H-1 1H-1I,4-benzodiazepin-2-one _______benzodiazepin-2-one (Example 8C-434 '-(L-alpha-hydroxyisocaproyl)- L-alpha-hydroxy isocaproic 3-[L-alaniny l)aminoj-2 C-J 451.5 L-alaninyl)amino]-2 ,3-dihydro- 1- acid dihydro- 1-methyl-5-(2-pyridyl)methyl-5-(2-pyridyl)- 1H- 1,4- (Aldrich) I H-i ,4-benzodiazepin-2-one iazepin-2-one C-AE) 8C-435 3-IN trophenylacetyl)-L- 3-nitrophenylacetic acid 3-[(L-alaninyl)aminol-2 C-J 500.5 alaninyl)aminol-2 ,3-dihydro- 1- (Aldrich) dihydro-i1-methyl-5-(2-pyridyl)methyl-5-(2-pyridyl)-1H-1 1 H-i ,4-benzodiazepin-2-one _______benzodiazepin-2-one 8C-436 3-[(N'-(D-3-phenylacetyl)-L- D-3-phenyllactic acid 3-IIL-alaninyl)aminoj-2,3- C-J 485.5 alaninyl)amino] 3-dihydro- 1- (Aldrich) dihydro-l1-methyl-5-(2-pyridyl)methyl-5-(2-pyridyl)-1H-1 111- 1,4-benzodiazepin-2-one _______benzodiazepin-2-one Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-437 3-II(N '-(4-methocyphenylacetyl)-L- 4-Methoxyphenylacetic 3-[(L-alaniny ])amino] -2,3 3- C-J 569.6 alaninyl)amino]-2,3-dihydro-l1-(3,3- acid dihydro- 1 3-dimethyl-2dimethyl-2-oxobutyl)- 5-(2-pyridyl)- (Aldrich) oxobutyl)- 5 -(2-pyridyl)- 1H- 1,4- II-i-I 1,4-benzodiazepin-2-one benzodiazepin-2-one 8C-438 3-II(N '-(2-thiopheneacetyl)-L- 2-Thiopheneacetic acid 3-[(L-alaninyl)amino]-2 C-J 545.6 alaninyl)aminol-2 ,3-dihydro-l1-(3,3- (Aldrich) dihydro- 3-dimethyl-2dimethyl-2-oxobutyl)- 5-(2-pyridyl)- oxobutyl)- 5-(2-pyridyl)-1H-1 ,4- 1 H-i ,4-benzodiazepin-2-one benzod iazepin-2-one (Example C-AG) 8C-439 ,5-difluorophenylacetyl)-L- 3 ,5-Difluorophenylacetic 3-[(L-alaninyl)amino]-2,3- C-J 575.6 alaninyl)aminol-2 ,3-dihydro-l1-(3,3- acid dihydro- 1 ,3-dimethyl-2dimethyl-2-oxobutyl)- 5-(2-pyridyl)- (Aldrich) oxobutyl)- 5-(2-pyridyl)- 1H- 1,4- I H-i ,4-benzodiazepin-2-one benzodiazepin-2-one
C-AG)
8C-440 '-(3-bromophenylacetyl)-L- 3-Bromophenylacetic acid 3+[L-alaninyl)aminol-2 C-J 618.5 alaninyl)aminoj-2 ,3-dihydro- (Aldrich) dihydro- 1 ,3-dimethyl-2d imethyl-2-oxobutyl)- 5-(2-pyridy oxobutyl)- 5-(2-pyridyl)-1H-1 ,4- 1 H-i ,4-benzodiazepin-2-one benzodiazepin-2-one Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-441 3-I(N'-(phenylmercaptoacetyl)-L- Phenylmercaptoacetic acid 3-[(L-alaninyl)amino]-2,3- C-J 571.7 alaninyl)amino]-2 ,3-dihydro-l1-(3,3- (Aldrich) dihydro-l1-(3 ,3-dimethyl-2dimethy 1-2-oxobutyl)- 5-(2-pyridyl)- oxobutyl)- 5-(2-pyridyl)-1H-1 ,4- 111-1 ,4-benzodiazepin-2-one benzod iazepin-2-one 8C-442 '-(4-ethoxyphenylacetyl)-L- 4-Ethoxyphenylacetic acid 3-[(L-alaninyl)amino]-2, 3- C-J 583.7 alaninyl)aminol-2 ,3-dihydro-l1-(3,3- (Aldrich) dihydro-l1-(3 ,3-dimethyl-2dimethyl-2-oxobutyl)- 5-(2-pyridyl)- oxobutyl)- 5-(2-pyridyl)-1H-1 ,4- 1 H-i ,4-benzodiazepin-2-one benzodiazepin-2-one C-AG) 8C-443 4- 3-I(L-alaninyl)aminol-2,3- C-J 607.6 (triluoromethyl)phenylacetyl)-L- (trifiuoromethyl)phenylacet dihydro-l1-(3,3 -dimethyl-2alaninyl)aminol-2 ,3-dihydro-l1-(3,3- ic acid oxobutyl)- 5-(2-pyridyl)- 1H- 1,4d imethyl-2-oxobuty 5-(2-pyridy (Aldrich) benzodiazepin-2-one 1H-1 ,4-benzodiazepin-2-one
C-AG)
8C-444 3 ,5-Bis(trifluoromethyl) 3-[(L-alaninyl)aiuinoJ-2 C-J 675.6 bis(trifluoromethyl)phenylacetyl)-L- phenylacetic acid dihydro-l1-(3 ,3-dimethyl-2alaninyl)aminol-2 ,3-dihydro-l1-(3,3- (Aldrich) oxobutyl)- 5-(2-pyridyl)-1 H-i ,4dimethyl-2-oxobutyl)- 5-(2-pyridyl)- benzodiazepin-2-one I_ 1 H-i ,4-benzodiazepin-2-one C-AG) Example Compound Starting Material 1 Starting Material 2 General MS No. 8C-445 '-((methylthio)acetyl)-L- (methylthio)acetic acid 3-[L-aianinyl)amino]-2 C-i 509.6 alaninyl)aminol-2,3-dihydro- 1 (Aldrich) dihydro-l1-(3 ,3-dimethyl-2dimethyl-2-oxobutyl)- 5-(2-pyridyl)- oxobutyl)- 5-(2-pyridyl)-1H-1 ,4- I H-I ,4-benzodiazepin-2-one benzod iazepin-2-one 8C-446 '-(cyclohexylacetyl)-L- cyclohexylacetic acid 3-IIL-alaninyi)aminoJ C-i 545.7 alaninyl)amino]-2 ,3-dihydro-l1-(3,3- (Aldrich) dihydro-l1-(3 ,3-dimethyl-2dimethyl-2-oxobutyl)- 5-(2-pyridyl)- oxobutyl)- 5-(2-pyridyl)-1H-1 ,4- I H-I ,4-benzodiazepin-2-one benzodiazepin-2-one
C-AG)
8C-447 '-(pentafluorophenoxyacetyl)- pentafluorophenoxyacetic 3-[(L-alaninyl)amino] C-J 645.6 L-aianinyl)aminoJ-2 ,3-dihydro- 1 acid dihydro- 1 ,3-dimethyl-2- 3-dimethyl-2-oxobutyl)- (Aldrich) oxobutyl)- 5-(2-pyridyl)- 1H- 1,4pyridyl)- IH-i ,4-benzodiazepin-2- benzodiazepin-2-one
C-AG)
8C-448 '-(benzo[blthiophene-3 -acetyl)- benzo thiophene-3- 3-[(L-alaniny l)aminoj-2 C-i 595.7 L-alaninyl)amino]-2,3-dihydro- 1 acetic acid dihydro- 1 3-dimethyl-2- 3-dimethyl-2-oxobutyl)- (Lancaster) oxobutyl)- 5-(2-pyridyl)-l1H- 1,4pyridyl)-1H-1 ,4-benzodiazepin-2- benzodiazepin-2-one C-AG) Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-449 2,4,6-trimethylphenylacetic 3-I(L-alaninyl)amino]-2,3- C-I 581.7 trimethylphenylacetyl)-L- acid dihydro-l1-(3, 3-dimethyl-2alaninyl)amino] 3-dihydro-l1-(3,3- (Lancaster) oxobutyl)- 5-(2-pyridyl)- 1H- 1,4dimethyl-2-oxobutyl)- 5-(2-pyridyl)- benzodiazepin-2-one 1 H-I ,4-benzodiazepin-2-one (Example 8C-450 3-II(N '-(4-biphenylacetyl)-L- 4-biphenylacetic acid 3-[(L-alaninyl)aminol-2 C-J 615.7 alaninyl)aminol-2 ,3-dihydro-l1-(3,3- (Lancaster) dihydro-l1-(3, 3-dimethyl-2dimethyl-2-oxobutyl)- 5-(2-pyridyl)- oxobutyl)- 5-(2-pyridyl)- 1H-i ,4- I H-i ,4-benzodiazepin-2-one benzodiazepin-2-one ___(Example C-AG) 8C-45 1 ,4-difluorophenylacetyl)-L- 3 ,4-difluorophenylacetic 3-[L-alaninyl)aminol-2 C-J 575.6 alaninyl)amino]-2 ,3-dihydro-l1-(3,3- acid dihydro-l1-(3 ,3-dimethyl-2dimethyl-2-oxobutyl)- 5-(2-pyridyl)- (Aldrich) oxobutyl)- 5-(2-pyridyl)-1H-1 ,4- I H-i ,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8C-452 3-[(N'-(4-(2-thienyl)btyl)-L- 4-(2-thienyl)butyric acid 3-[(L-alaninyl)aminoj-2,3- C-I 573.7 alaninyl)amino]-2 ,3-d ihydro-l1-(3,3- (Aldrich) dihydro- 1 ,3-dimethyl-2dimethyl-2-oxobutyl)- 5-(2-pyridyl)- oxobutyl)- 5-(2-pyridyl)-IH-1 ,4-1 1 H-i ,4-benzodiazepin-2-one benzod iazepin-2-one (ExampleC-AG)_ Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-453 3-[(N'-(5-methylhexanoyl)-L- 5-methyihexanoic acid 3-[(L-alaninyl)amino]-2,3- C-J 533.7 alaninyl)aminol-2, 3-dihydro-l1-(3,3- dihydro- 1 ,3-dimethyl-2dimethyl-2-oxobutyl)- 5-(2-pyridyl)- oxobutyl)- pyridyI)-1H-1 ,4- I fl-i ,4-benzodiazepin-2-one benzodiazepin-2-one
C-AG)
8C-454 mono-methyl succinate 3-[(L-alaninyl)amino]-2,3- C-J 535.6 methoxycarbonylpropionyl)-L- (Aldrich) dihydro- 1-(3 ,3-dimethyl-2alaninyl)aminoJ-2,3-dihydro-l1-(3,3- oxobutyl)- 5-(2-pyridyl)- 1H-i ,4dimethyl-2-oxobutyl)- 5-(2-pyridyl)- benzodiazepin-2-one I H-i ,4-benzodiazepin-2-one 8C-455 '-(methanesulfonylacetyl)-L- methanesulfonylacetic acid 3-[L-alaniny l)aminoJ-2 C-J 541.6 alaniny ])amino]l-2,3 -d ihydro- 1 (Lancaster) dihydro-1 ,3-dimethyl-2dimethyl-2-oxobutyl)- 5-(2-pyridyl)- oxobutyl)- 5-(2-pyridyl)-IH- 1,4- I H-i ,4-benzodiazepin-2-one benzodiazepin-2-one
C-AG)
8C-456 '-(4-toluenesuifonylacetyl)-L- 4-toluenesulIfonylIacetic 3-+L-alaninyl)aniino]-2, 3- C-J 617.7 alaninyl)aminoj-2 ,3-dihydro-l1-(3,3- acid dihydro-l1-(3 ,3-dimethyl-2dimethyl-2-oxobutyl)- 5-(2-pyridyl)- (Lancaster) oxobutyl)- 5-(2-pyridyl)- 1H- 1,4- 1 H-i ,4-benzodiazepin-2-one benzodiazepin-2-one (ExampleC-AG) Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-457 3-IN ,6-difluoromandelyl)-L- 2 ,6-difluoromandelic acid 3-IL-alaninyl)amino]-2 C-J 591.6 alaninyl)amino]-2,3-dihydro- 1 (Fluorochem) dihydro- 1 3-dimethyl-2dimethyl-2-oxobutyl)- 5-(2-pyridyl)- oxobutyl)- 5-(2-pyridyl)-iH-1 14- I H-i ,4-benzodiazepin-2-one benzodiazepin-2-one
C-AG)
8C-458 '-(4-fluoromandelyl)-L- 4-fluoromandelic acid 3-[(L-alaninyl)amino]-2 C-J 573.6 alaninyl)amino]-2 ,3-dihydro-l1-(3,3- (Lancaster) dihydro- 1 3-dimethyl-2dimethyl-2-oxobutyl)- 5-(2-pyridyl)- oxobutyl)- 5-(2-pyridyl)-iH-1 ,4- I H-i ,4-benzodiazepin-2-one benzod iazepin-2-one C-AG) 8C-459 3-[N'-(2,5-difluoromandelyl)-L- 2,5-difluoromandelic acid 3-[L-alaninyl)aminoj-2 C-J 591.6 alaninyl)amino]-2,3-dihydro- 1 (Fluorochem) dihydro- 1 ,3-dimethyl-2dimethyl-2-oxobutyl)- 5-(2-pyridyl)- oxobutyl)- 5-(2-pyridyl)-l1H-i ,4- 1 H-I ,4-benzodiazepin-2-one benzodiazepin-2-one C-AG) 8C7460 3-II(N ,4,6-trifluorophenylacetyl)- 2,4,6-trifluoroplienylacetic 3-[(L-alaninyl)aminoJ-2 C-J 593.6 L-alaninyl)aminoj-2,3-dihydro- 1- acid dihydro- 1-(3 ,3-dimethyl-2- 3-dimethyl-2-oxobutyl)- (Fluorochem) oxobutyl)- 5-(2-pyridyl)- 1H- 1,4pyridyl)- 1 H-i ,4-benzodiazepin-2- benzodiazepin-2-one one (Example C-AG) Example Compound Starting Material 1 Starting Material 2 General MS0 No. Proc .edure 8C-461 3-[(N'-(4-fluoro-2- 4-fluoro-2- 3 -tI(L-alaninyl)aminojj-2,3- C-J 625.6 (trifluoromethyl)phenylacetyl)-L.. (trifluoromethyl) dihydro- 1 ,3-dimethyl-2alaninyl)aminoJ-2 ,3-dihydro- phenylacetic acid oxobutyl)- 5-(2-pyridyl)- 1H- 1,4dimethyl-2-oxobutyl)- 5-(2-pyridyl)- (Fluorochem) benzodiazepin-2-one 1H-i ,4-benzodiazepin-2-one
C-AG)
8C-462 ,4-trifluorobutyryl)-L- 4,4 ,4-trifluorobutyric acid 3-IIL-alaninyl)amino] C-J 545.5 alaninyl)aminoj-2 ,3-dihydro-l1-(3,3- (Fluorochem) d ihydro-l1-(3 ,3-dimethyl-2dimethyl-2-oxobutyl)- 5-(2-pyridyl)- oxobutyl)- 5-(2-pyridyl)-1H-1 14-* 1 H-i ,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AG) 8C-463 3-[(N'-(4-isopropylphenylacetyl)-L- 4 -isopropylphenylacetic 3-[L-alaninyl)aminoJ-2 C-J 581.7 alaninyl)amino]-2,3-dihydro-l1-(3,3- acid dihydro-l1-(3, 3-dimethyl-2dimethyl-2-oxobutyl)- 5-(2-pyridyl)- (Lancaster) oxobutyl)- 5-(2-pyridyl)- IH- 1,4- 1 H-I ,4-benzodiazepin-2-one benzodiazepin-2-one (Examnple C-AG) 8C-464 '-(beta-phenyl lactyl)-L- beta-phenyllactic acid 3-[(L-alaninyl)amino]-2 C-J 569.6 alaninyl)aminoJ-2 ,3-dihydro-l1-(3,3- (Sigma) dihydro- 1-(3 ,3-dimethyl-2dimethyl-2-oxobutyl)- 5-(2-pyridyl)- oxobuty 5-(2-pyridyl)- 1H-I ,4- IH- 1,4-benzodiazepin-2-one benzodiazepin-2-one Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-465 '-(mandelyl)-L- mandelic acid 3-[(L-alaninyl)amino]-2,3- C-J 555.6 alaninyl)amino]-2 ,3-dihydro-l1-(3,3- (Aldrich) dihydro-l1-(3, 3-dimethyl-2dimethyl-2-oxobutyl)- 5-(2-pyridyl)- oxobutyl)- 5-(2-pyridyl)-1H-1 ,4- 1H-1 ,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AG) 8C-466 3-RN'-(4-chloromandelyl)-L- p-chloromandelic acid 3-[(L-alaninyl)amino]-2,3- C-J 590.1 alaninyl)amino]-2,3-dihydro-l1-(3,3- (Acros) dihydro- 1-(3 ,3-dimethyl-2dimethyl-2-oxobutyl)- 5-(2-pyridyl)- oxobutyl)- 5-(2-pyridyl)-1H-1 ,4- 1H-1 ,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AG) 8C-467 '-(isovaleryl)-L- isovaleric acid 3-[L-alaninyl)aminol-2,3- C-J 505.6 alaninyl)amino] 3-dihydro-l1-(3,3- (Aldrich) dihydro-l1-(3 ,3-dimethyl-2dimethyl-2-oxobutyl)- 5-(2-pyridyl)- oxobutyl)- 5-(2-pyridyl)-1H-1 ,4- 111-1 ,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AG) 8C-468 5-trifluorophenylacetyl)- 2,3, 5-trifluorophenylacetic 3-[(L-alaninyl)amino]-2 C-J 593.6 L-alaninyl)amino]-2 ,3-dihydro- 1- acid dihydro- 1-(3 ,3-dimethyl-2- 3-dimethyl-2-oxobutyl)- (Fluorochem) oxobutyl)- 5-(2-pyridyl)- 1H- 1,4pyridyl)-1 H-i ,4-benzodiazepin-2- benzodiazepin-2-one C-AG) Example Compound Starting Material 1 Starting Material 2 General MS No. 8C-469 3-I(N '-(3-methylthiopropionyl)-L- 3-methyithiopropionic acid 3-[(L-alaninyl)amino]-2,3- C-J 523.6 alaninyl)aminol-2,3-dihydro- 1 (Lancaster) dihydro- I 3-dimethyl-2dimethyl-2-oxobutyl)- 5-(2-pyridyl)- oxobutyl)- 5-(2-pyridyl)-1H-1 ,4- 1 H-i ,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AG) 8C-470 '-(L-alpha-hydroxyisocaproyl)- L-alpha-hydroxyisocaproic 3-[(L-alaninyl)amino]-2 C-J 535.6 L-alaninyl)amino]-2 ,3-dihydro- 1- acid dihydro- 1 3-dimethyl-2- (3 ,3-dimethyl-2-oxobutyl)- (Aldrich) oxobutyl)- 5-(2-pyridyl)- 1H- 1,4pyridyl)- 1H-i ,4-benzodiazepin-2- benzodiazepin-2-one (Example 8C-47 1 '-(3-nitrophenylacetyl)-L- 3-nitrophenylacetic acid 3-[L-alaninyl)amino]-2 C-J 584.6 alaninyl)amino]-2 ,3-dihydro-l1-(3,3- (Aldrich) dihydro- 1 ,3-dimethyl-2dimethyl-2-oxobutyl)- 5-(2-pyridyl)- oxobutyl)- 5-(2-pyridyl)-1H-1 ,4- 1 H-i ,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AG) 8C-472 3-[(N'-(D-3-phenyllactyl)-L- D-3 -phenyl lactic acid 3-[L-alaninyl)aminol-2,3- c-i 569.6 alaninyl)aminoJ-2,3-dihydro-1 (Aldrich) dihydro-l1-(3 ,3-dimethyl-2dimethyl-2-oxobutyl)- 5-(2-pyridyl)- oxobutyl)- 5-(2-pyridyl)-1H-1 ,4- 1H- 1,4-benzodiazepin-2-one benzodiazepin-2-one (ExampleC-AG) Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-473 '-(4-methoxyphenylacetyl)-L- 4-Methoxyphenylacetic 3-[L-alaninyl)amino]-2 C-J 570.7 alaninyl)amino]-2 ,3-dihydro- 1 acid dihydro- 1 N-diethyl N,N-diethyl aminoethyl)- (Aldrich) aminoethyl)- 5-(2-pyridyl)-1Hpyridyl)-1 H-i ,4-benzodiazepin-2- 1 ,4-benzodiazepin-2-one _____(Example 8C-474 3-II(N '-(2-thiopheneacetyl)-L- 2-Thiopheneacetic acid 3-[(L-alaninyl)amino] C-J 546.7 alaninyl)aminoj-2 ,3-dihydro-1 (Aldrich) dihydro-1 N-diethyl N,N-diethyl aminoethyl)- aminoethyl)- 5-(2-pyridyl)- 1Hpyridyl)-IH-1 ,4-benzodiazepin-2- I ,4-benzodiazepin-2-one (Example C-AF) 8C-475 -acetyl-N N-acetyl-N-phenylglycine 3-[L-alaninyl)aminol-2 C-J 597.7 phenylglycinyl)L-alaniny l)amino]- (Kodak) dihydro- 1-(2-N ,N-diethyl 2,3-dihydro-l1-(2-N ,N-diethyl aminoethyl)- 5-(2-pyridyl)-1Haminoethyl)- 5-(2-pyridyl)- 1H- 1,4- 1 ,4-benzod iazep in-2 -one benzodiazepin-2-one
C-AF)
8C-476 3-17(N ,5-difluorophenylacetyl)-L- 3 ,5-Difluorophenylacetic 3-I(L-alaninyl)aminol-2 C-J 576.6 alaninyl)aminol-2,3-dihydro-1 acid dihydro-l1-(2-N ,N-diethyl N,N-diethyl aminoethyl)- (Aldrich) aminoethyl)- 5-(2-pyridyl)-1Hpyridyl)-1H-1 ,4-benzodiazepin-2- I ,4-benzodiazepin-2-one C-AF) Example Compound Starting Material 1 Starting Material 2 General MS No. 8C-477 '-(3-bromophenylacetyl)-L- 3-Bromophenylacetic acid 3-[(L-alaninyl)amino]-2, 3- C-J 619.6 alaninyl)amino]-2,3-dihydro- (Aldrich) dihydro-l1-(2-N ,N-diethyl N,N-diethyl aminoethyl)- aminoethyl)- 5-(2-pyridyl)- 1Ipyridyl)- 111-1 ,4-benzodiazepini-2- I ,4-benzodiazepin-2-one _____(Example C-AF) 8C-478 3- -(phenylmcercaptoacetyl)-L- Phenylmercaptoacetic acid 3-IIL-alaninyl)aminol-2 C-J 572.7 alaninyl)amino]-2 ,3-dihydro-l1-(2- (Aldrich) dihydro-lI-(2-N, N-diethyl N,N-diethyl aminoethyl)- aminoethyl)- 5-(2-pyridyl)-1Hpyridyl)-1H-1 ,4-benzodiazepin-2- 1 ,4-beazodiazepin-2-one one
C-AF)
8C-479 3 -(4-ethoxypheny lacety 4-Ethoxyphenylacetic acid 3-[(L-alaninyl)amino]-2 C-J 584.7 aianinyl)aminol-2 ,3-dihydro-l1-(2- (Aldrich) dihydro-l1-(2-N ,N-diethyl N,N-diethyl aminoethyl)- aminoethyl)- 5-(2-pyridyl)- 1Hpy ridy1)-i H-i ,4-benzodiazepin-2- 1 ,4-benzodiazepin-2-one (Example C-AF) 8C-480 4- 3-[(L-alaninyl)amino]-2 C-J 608.7 (tri fluoromethyl)phenylacetyl)-L- (trifluoroniethyl)phenylacet dihydro-lI-(2-N, N-diethyl alaninyl)amino]-2,3-dihydro- ic acid aminoethyl)- 5-(2-pyridyl)-1H- N, N-diethyl aminoethyl)- (Aldrich) 1 ,4-benzodiazepin-2-one pyridyl)-1IH- 1,4-benzodiazepin-2- (Example C-AF) oneIIII Example Compound Starting Material 1 Starting Material 2 General MS No. 8C-481 3,5-IBis(ti-ifluoromethyl) 3-[L-alaninyl)amino]-2,3- C-i 676.7 bis(trifluoromethyl)phenylacetyl)-L- phenylacetic acid dihydro- N-diethyl alaninyl)amino]-2 ,3-dihydro-l1-(2- (Aldrich) aminoethyl)- 5-(2-pyridyl)- 1H- N,N-diethyl aminoethyl)- I ,4-benzodiazepin-2-one pyridyl)-1 11-1 ,4-benzodiazepin-2- (Example C-AF) one 8C-482 3- -((methylthio)acetyl)-L- (methylthio)acetic acid 3-[L-alaninyl)aminol C-I 510.6 alaninyl)amino]-2 ,3-dihydro- (Aldrich) dihydro-l1-(2-N, N-diethyl N,N-diethyl aminoethyl)- aminoethyl)- 5-(2-pyridyl)-1Hpyridyl)- 1H-i ,4-benzodiazepin-2- 1 ,4-benzodiazepin-2-one C-AF) 8C-483 3-[N'-(cyclohexylacetyl)-L- cyclohexylIacetic acid 3-I(L-alaninyl)amino]-2,3- C-J 546.7 alaninyl)aminoj-2 ,3-dihydro- 1 (Aldrich) dihydro- 1 ,N-diethyl 00 N,N-diethyl aminoethyl)- aminoethyl)- 5-(2-pyridyl)-1Hpyridyl)-1H-1 ,4-benzodiazepin-2- 1 ,4-benzodiazepin-2-one one
C-AF)
8C-484 '-(pentafluorophenoxyacetyl)- pentafluorophenoxyacetic 3-[(L-alaninyl)amino]-2 C-I 646.6 L-alaninyl)amino]-2, 3-dihydro- 1 acid dihydro- 1 N-d iethyl N,N-diethyl aminoethyl)- (Aldrich) aminoethyl)- 5-(2-pyridyl)-1Hpyridyl)-1H-1 ,4-benzodiazepin-2- 1 ,4-benzodiazepin-2-one _____(Example Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-485 3- -(benzo[b]thiophene-3-acetyl)- benzo thiophene-3- 3-Ii(L-alaninyl)amino]-2 C-J 596.7 L-alaninyl)aminoj-2 ,3-dihydro-l1-(2- acetic acid dihydro- 1-(2-N ,N-diethyl N, N-diethyl aminoethyl)- (Lancaster) aminoethyl)- 5-(2-pyridyl)- 1Hpyridyl)-1H-1 ,4-benzodiazepin-2- I ,4-benzodiazepin-2-one one (Example 8C-486 3-[(N'-(benzoylformyl)-L- benzoylformic acid 3-[(L-alaninyl)amino]-2,3- C-J 554.6 alaninyl)amino]-2 ,3-dihydro-l1-(2- (Aldrich) dihydro-l1-(2-N,N-diethyl N,N-diethyl aminoethyl)- aminoethyl)- 5-(2-pyridyl)- 1Hpyridyl)- 1 H-i ,4-benzodiazepin-2- 1 ,4-benzodiazepin-2-one one C-AF) 8C-487 3-[I(N 2 ,4,6-trimethylpheny Iacetic 3-[L-alaninyl)aminoj-2,3- C-J 582.7 trimethylphenyhlacetyl)-L- acid dihydro-1-(2-N,N-diethyl alaninyl)aminol-2 ,3-dihydro-l1-(2- (Lancaster) aminoethyl)- 5-(2-pyridyl)- IH- N,N-diethyl aminoethyl)- 1 ,4-benzodiazepin-2-one pyridyl)-1H-1 ,4-benzodiazepin-2- (Example C-AF) one 8C-488 '-(4-biphenylacetyl)-L- 4-biphenylacetic acid 3-[(L-alaninyl)aminoj-2 C-J 616.8 a Ian inylI)amino] -2 ,3-dihydro- 1 (Lancaster) dihydro- 1 N-diethyl N,N-diethyl aminoethyl)- aminoethy 5 -(2-pyridyl)- IHpyridyl)- 1H-i ,4-benzodiazepin-2- 1 ,4-benzodiazepin-2-one _____(Example C-AF) Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-489 ,4-difluorophenylacetyl)-L- 3 ,4-ditluorophenylacetic 3-[L-alaninyl)amino]-2 C-J 576.6 alaninyl)amino]-2 ,3-dihydro- 1 acid dihydro- 1 ,N-diethyl N,N-diethyl aminoethyl)- (Aldrich) aninoethyl)- 5-(2-pyridyl)-1Hpyridyl)-1 H-I ,4-benzodiazepini-2- I ,4-benzodiazepin-2-one one (Example C-AF) 8C-490 '-(4-(2-thienyl)butyryl)-L- 4-(2-thienyl)butyric acid 3+[L-alaninyl)aminol-2,3- C-J 574.7 alaninyl)aminol-2,3-dihydro-l1-(2- (Aldrich) dihydro-l1-(2-N,N-diethyl N,N-diethyl aminoethyl)- aminoethyl)- 5-(2-pyridyl)-1 Hpyridyl)-IH-1 ,4-benzodiazepin-2- I ,4-benzodiazepin-2-one 8C-491 3-[(N'-(5-methylhexanoyl)-L- 5-methyihexanoic acid 3-[(L-alaninyl)amino]-2,3- C-J 534.7 alaninyl)aminol-2 ,3-dihydro-l1-(2- dihydro- 1-(2-N ,N-diethyl N,N-diethyl aminoethyl)- aminoethyl)- 5-(2-pyridyl)-1Hpyridyl)-1 H-i ,4-benzodiazepin-2- 1 ,4-benzodiazepin-2-one _____(Example
C-AF)
8C-492 mono-methyl succinate 3-[(L-alaninyl)amino]-2,3- C-J 536.6 methoxycarbonylpropionyl)-L- (Aldrich) dihydro-l1-(2-N,N-diethyl alaninyl)amino]-2 ,3-dihydro-l1-(2- aminoethyl)- 5-(2-pyridyl)-1H- N,N-diethyl aminoethyl)- 1 ,4-benzodiazepin-2-one pyridyl)- IH-I ,4-benzodiazepin-2- (Example C-AF) Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-493 3-II(N '-(methanesulfonylacetyl)-L- methanesulfonylacetic acid 3-[(L-alaninyl)aminol-2 C-J 542.6 alaninyl)aminol-2 ,3-dihydro- (Lancaster) dihydro-l1-(2-N, N-diethyl N,N-diethyl aminoethyl)- aminoethyl)- 5-(2-py.ridyl)-1Hpyridyl)-1IH- 1,4-benzodiazepin-2- I ,4-benzodiazepin-2-one one 8C-494 '-(4-toluenesulfonylacetyl)-L- 4-toluenesulfonylacetic 3-[(L-alaninyl)aminoj-2 C-J 618.7 alaninyl)aminol-2,3-dihydro- 1 acid dihydro- 1 N-diethyl N,N-diethyl aminoethyl)- (Lancaster) aminoethyl)- 5-(2-pyridyl)-IHpyridyl)-iH-1 ,4-benzodiazepin-2- 1 ,4-benzodiazepin-2-one _____(Example 8C-495 ,6-difluoromandelyl)-L- 2 ,6-difluoromandelic acid 3-[(L-alaninyl)aminol-2,3- C-J 592.6 alaninyl)aminol-2 ,3-dihydro-l1-(2- (Fluorochem) d ihydro-l1-(2-N, N-diethyl N,N-diethyl aminoethyl)- aminoethyl)- 5-(2-pyridyl)-1Hpyridyl)- I H-i,4-benzodiazepin-2- 1 ,4-benzodiazepin-2-one (Example C-AF) 8C-496 3 -(4-fluoromandely 4-fluoromandelic acid 3 -[(L-alaninyl)amino]-2 C-J 574.6 alaninyl)aminol-2 ,3-dihydro- 1 (Lancaster) dihydro- 1 N-diethyl N,N-diethyl aminoethyl)- aminoethyl)- 5-(2-pyridyl)- 1Hpyridyl)-IH-1 ,4-benzodiazepin-2- I ,4-benzodiazepin-2-one _____(Example Example Compound Starting Material I Starting Material 2 General MS 0 8C-497 3-tN ,5-difluoromandelyl)-L- 2,5-difluoromandelic acid 3-[(L-alaninyl)aminol-2 C-J 592.6 alaninyl)aminoj-2 ,3 -dihydro-l1-(2- (Fluorochem) dihydro-l1-(2-N, N-diethyl N,N-diethyl aminoethyl)- aminoethyl)- 5-(2-pyridyl)- 1Hpyridyl)-1H-1 ,4-benzodiazepin-2- 1 ,4-benzodiazepin-2-one one
C-AF)
8C-498 4- 3 -[(L-alaninyl])amino] C-J 586.7 (hydroxymethyl)phenoxyacetyl)-L- (hydroxymethyl)phenoxyac dihydro-l1-(2-N, N-diethyl alaninyl)amino]-2,3-dihydro-1-(2- etic acid aminoethyl)- 5-(2-pyridyl)-1H- N,N-diethyl aminoethyl)- (Sigma) 1 ,4-benzodiazepin-2-one pyridyl)-1H-1 ,4-benzodiazepin-2- (Example C-AF) 8C-499 6-trifluorophenylacetyl)- 2,4 ,6-trifluorophenylacetic 3-[(L-alaninyl)aminoj-2, 3- C-I 594.6 L-alaninyl)aminoj-2,3-dihydro-1 acid dihydro-l1-(2-N ,N-diethyl N,N-diethyl aminoethyl)- (Fluorocliem) aminoethyl)- 5-(2-pyridyl)-1Hpyridyl)-1Il- 1,4-benzodiazepin-2- 1 ,4-benzodiazepin-2-one one 8C-500 '-(4-tluoro-2- 4-fluoro-2- 3-IIL-alaninyl)aminol-2,3- C-I 626.6 (tr-ifluoromethyl)phenyiacetyl)-L- (tri fluoromethyl) dihydro-l1-(2-N, N-d iethyl alaninyl)amino]-2 ,3-dihydro- 1 phenylacetic acid aminoethyl)- 5-(2-pyridyl)- 1H- N, N-diethyl aminoethyl)- (Fluorochem) 1 ,4-benzodiazepin-2-one pyridyl)-1IH- 1,4-benzodiazepin-2- (Example C-AF) Example Compound Starting Material 1 Starting Material 2 General MIS No. Procedure 8C-501 '-(4,4,4-trifluorobutyryl)-L- 4 ,4,4-trifluorobutyric acid 3-I(L-alaninyl)aminol-2,3- C-J 546.6 alaninyl)amino]-2 ,3-dihydro-l1-(2- (Fluorochem) dihydro-l1-(2-N, N-diethyl N,N-diethyl aminoethyl)- aminoethyl)- 5-(2-pyridyl)-1Hpyridyl)-IH-1 ,4-benzodiazepin-2- 1 ,4-benzodiazepin-2-one one 8C-502 3-[(N'-(4-isopropylphenylacetyl)-L- 4-isopropylphenylacetic 3+[L-alaninyl)aminoj-2 ,3 C-J 582.7 alaninyl)aminoj-2 ,3-dihydro-l1-(2- acid dihydro-l1-(2-N, N-d jethyl N, N-diethyl aminoethyl)- (Lancaster) aminoethyl)- 5-(2-pyridyl)- 1Hpyridyl)-1H-1 ,4-benzodiazepin-2- 1 ,4-benzodiazepin-2-one one 8C-503 3-[(N'-(beta-phenyllactyl)-L- beta-phenyllactic acid 3-[L-alaninyl)amino]-2,3- C-J 570.7 alaninyl)aminoj-2 ,3-dihydro-1 (Sigma) dihydro-l1-(2-N,N-diethyl N,N-diethyl aminoethyl)- aminoethyl)- 5-(2-pyridyl)-1Hpyridyl)- IH-i ,4-benzodiazepin-2- 1 ,4-benzodiazepin-2-one (Example C-AF) 8C-504 3-[(N'-(mandelyl)-L- mandelic acid 3-[(L-alaninyl)amino]-2,3- C-J 556.7 alaninyl)amino]-2 ,3-dihydro-l1-(2- (Aldrich) dihydro-l1-(2-N, N-diethyl N,N-diethyl aminoethyl)- aminoethyl)- 5-(2-pyridyl)-1Hpyridyl)- 1H-i ,4-benzodiazepin-2- 1 ,4-benzodiazepin-2-one C-AF) Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 00_ 8C-505 3-IN'-(4-chloromandelyl)-L- p-chloromandelic acid 3-[(L-alaninyl)amino]-2,3- C-J 591.1 alaninyl)aminoJ-2 ,3-dihydro-l1-(2- (Acros) dihydro-l1-(2-N ,N-diethyl 0 N,N-diethyl aminoethyl)- aminoethyl)- 5-(2-pyridyl)-1Hpyridyl)-IH-1 ,4-benzodiazepin-2- 1 ,4-benzodiazepin-2-one
C-AF)
8C-506 3-I(N'-(isovaleryl)-L- isovaleric acid 3-[(L-alaninyl)amino]-2,3- C-J 506.6 alaninyl)amino]-2 ,3-dihydro-l1-(2- (Aldrich) dihydro-l1-(2-N,N-diethyl N,N-diethyl aminoethyl)- aminoethyl)- 5-(2-pyridyl)-iHpyridyl)-1H-1 ,4-benzodiazepin-2- 1 ,4-benzodiazepin-2-one (Example C-AF) 8C-507 3,5-trifluorophenylacetyl)- 2,3 ,5-trifluorophenylacetic 3-[(L-alaninyl)amino]-2 C-J 594.6 L-alaninyl)aminoj-2 ,3-dihydro- acid dihydro-l1-(2-N, N-diethyl N ,N-diethyl aminoethyl)- (Fluorochem) aminoethyl)- 5-(2-pyridyl)-l1Hpyridyl)-iH-1 ,4-benzodiazepin-2- I ,4-benzodiazepin-2-one (Example 8C-508 '-(3-methylthiopropionyl)-L- 3-methylthiopropionic acid 3-[(L-alaninyl)aminoj-2,3- C-J 524.7 alaninyl)aminoj-2 ,3 -dihydro-l1-(2- (Lancaster) dihydro-l1-(2-N, N-diethyl N,N-diethyl aminoethyl)- aminoethyl)- 5-(2-pyridyl)-1 Hpyridyl)-l H-i ,4-benzodiazepin-2- 1 ,4-benzodiazepin-2-one C-AF) Example Compound Starting Material I Starting Material 2 General MS No. Procedure 8C-509 3-[(N'-(L-alpha-hydroxyisocaproyl)- L-alpha-hydroxyisocaproic 3-[(L-alaninyl)amino]-2 C-J 536.7 L-alaninyl)aminoj-2,3-dihydro-l1-(2- acid dihydro-l1-(2-N ,N-diethyl N, N-diethyl aminoethyl)- (Aldrich) aminoethyl)- 5-(2-pyridyl)- 1Hpyridyl)-1H-l ,4-benzodiazepin-2- I ,4-benzodiazepin-2-one (Example 10 3-II(N '-(3-nitrophenylacetyl)-L- 3-nitrophenylacetic acid 3-[(L-alaninyl)aminoj-2,3- C-J 585.7 alaninyl)amino]-2,3-dihydro-l1-(2- (Aldrich) dihydro-l1-(2-N,N-diethyl N,N-diethyl aminoethyl)- aminoethyl)- 5-(2-pyridyl)-1 Hpyridyl)-1H-1 ,4-benzodiazepin-2- 1 ,4-benzodiazepin-2-one _____(Example 11 '-(D-3-phenyllactyl)-L- D-3-phenyl lactic acid 3-[(L-alaninyl)aminoj-2 C-J 570.7 alaninyl)amino]-2,3-dihydro-l1-(2- (Aldrich) dihydro-lI-(2-N, N-diethyl N,N-diethyl aminoethyl)- aminoethyl)- 5-(2-pyridyl)- IHpyridyl)-l1H-i ,4-benzodiazepin-2- 1 ,4-benzodiazepin-2-one _____(Example C-AF) WO 98/28268 PTU9128 PCTIUS97/22986 536 GENERAL PROCEDURE C-L The following amino acids were employed in this procedure: L-alanine (Aldrich), L-valine (Aldrich), L-norvaline (Aldrich), L-methione (Aldrich), Lphenylalanine (Aldrich), +)-ci-phenylglycine (Aldrich), L-a-(2thienyl)glycine (Sigma), L-a-(3-thienyl)glycine (Sigma), L-cyclohexylglycine hydrochloride (Senn Chemical AG), O-tert-butyl-L-serine (Sigma), O-tert-butyl- L-threonine (Bachem) and O-tert-butyl-L-tyrosine (Bachem).
The amino acid (60 /imoles), 305 mg (150 umoles) of N,O- -bistrimethylsilylacetamaide and 1.5 mL of DMF were introduced into separate fritted screw capped vials. The mixtures were heated mildly and upon cooling 132 mg (15 jmoles) of p-nitrophenylcarbonate Wang resin (actual load of 1.14 mmole/g) (Novabiochem) was added to the individual vials. In addition, 73 mg mmoles) of dimethylaminopyridine was introduced into vials containing Lcyclohexylglycine hydrochloride. The vials were shaken at room temperature for 48 hours. Each reation mixture was filtered through the internal frit and the resulting resin was washed with (9 x 1.0 mL) of DMF, (9 x 1.0 mL) of methanol and (6 x 1.0 mL) of diethyl ether. Each reaction vial containing the resin bound amino acid was then dried in a vacuum oven at GENERAL PROCEDURE C-M Into each fritted screw capped vial containing a resin bound amino acid (from General Procedure C-L) was introduced 81 mg (60 jimoles) of 1hydroxybenzotriazole hydrate (HOBT 115 mg (60 Amoles) of 1-(3dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC HCI), and 2 mL of THF. A 3-amino-2,4-dioxo- 1, 5-bis-(alkyl)-2 ,3 ,4,5-tetrahydro- 1H- benzodiazepin (30 j~moles) selected from 3-aniino-2 ,4-dioxo- 1,5-bis(2methylpropyl)-2,3,4,5-tetrahydro-lH-1,5-benzodiazepin (Example 8S, Step C), 3-amino-2 ,4-dioxo- 1,5-bis(methyl)-2 5-tetrahydro- 1H- (Example 8-R, Step C) and 3 -axnino-2,4-dioxo-1,5-bis(cyclopropylmethyl)- 2,3,4,5-tetrahydro-1H-1,5-benzodiazepin (Example 8-U, Step C) was added to WO 98/28268 PCT/US97/22986 537 the vials. Each vial was then capped and shaken at room temperature for 4 days. Each reaction mixture was filtered through the internal frit and the resulting resin was washed with (3 x 2.0 mL) of DMF, (3 x 2.0 mL) of a 10 solution of acetic acid in methanol, (3 x 2.0 mL) of a 10 solution of acetic .acid in THF, and (3 x 2.0 mL) of a 10 solution of acetic acid in dichloromethane.
GENERAL PROCEDURE
C-N
Each resin from General Procedure C-M was suspended in 2.0 mL of trifluoroacetic acid for 30 minutes. Each reaction was filtered through the internal frit into a 10 mL vial and the resin was washed with (3 x 1.0 mL) of methanol. The filtrate was concentrated under a flow of nitrogen at 30°C. The concentrated residue was dissolved in 1.5 mL of methanol and partitioned into 3 portions. Each portion was subjected to affinity chromotography on a pretreated SCX column (pretreatment consisted of flushing with 2 mL of a solution of acetic acid in methanol followed by 2 mL of methanol). Once loaded, all columns were flushed with 5 mL of methanol, discarding each wash.
Each compound was liberated from the column with 5 mL of a 1 N solution of ammonia in a 1/1 solution of methanol and chloroform. Each solution was transferred to a tarred vial followed by concentration under a stream of nitrogen, followed by final concentration under vacuum.
GENERAL PROCEDURE C-O To each vial containing a specific amino acid benzodiazepine (from General Procedure C-N) was added 1 mL of a 0.4 M solution of 1-(3dimethylaminopropyl)-3-ethyl-carbodiimide (EDC) and 0.9 equivalents of a carboxylic acid selected from 3,5-difluorophenylacetic acid, cyclopentylacetic acid and 4 ,4,4-trifluorophenylacetic acid. The vials were capped and shaken for 4 days. Each reaction was then concentrated under a continuous flow of nitrogen. The residue was subjected to affinity chromotography on a pretreated SCX column (pretreatment consisted of flushing with 2 mL of a 10 solution WO 98/28268 PCT/US97/22986 538 of acetic acid in methanol followed by 2 mL of methanol). Once loaded, all columns were eluted with 5 mL of methanol. Each solution was transferred to a tarred vial followed by concentration under a stream of nitrogen with final concentration under vacuum.
Using the procedures indicated, the compounds shown in Table C-3 were prepared. In this table, Starting Material 1 was prepared using General Procedures C-L, C-M and C-N. 3 ,5-Difluorophenylacetic acid and cyclopenylacetic acid are available from Aldrich, and 4 ,4,4-trifluorobutyric acid is available from Fluorochem.
Table C-3 Example No._ 8C-512 8C-513 8C-514 Compound Starting Material 1 Starting Material 2 General ,5-Difluorophenylacetyl)-LalaninyllI-amino-2,4-dioxo- 1,5-b is- (2-mtyprp 5-tetrahydro I H 5b diein ,5-Difluorophenylacetyl)-LalaninylJ-amino-2,4-dioxo-1 ,5-bis- (methyl)-2,3 ,4,5-tetrahydro- I H- 1,5 -benzodiazepine Procedure 4- 3-(L-Alaninyl)-am-ino-2,4dioxo-1 ,5-bis-(2methylpropyl)-2,3,4,5tetrahyclro-1H-1 benzod iazepine 3-(L-Alaninyl)-amino-2 ,4dioxo- 1,5-bis-(methyl)- 2,3,4,5-tetrahydro-1IH- benzodiazepine 3, 5-Difluorophenylacetic Acid c-0 529.2 I 3 ,5-Difluorophenylacetic Acid 3 ,5 -Di fluoropheny Iacetic Acid C-a 445.1 ,5-Difluorophenylacetyl)-LalaninylJ-amino-2,4-dioxo-1 ,5-bis- (cyclopropylmethyl)-2 ,3,4 ,5-tetrahy dro-lH-1 ,5-benzodiazepine 3-(L-Alaninyl)-amino-2,4dioxo-1 ,5-bis- (cyclopropylmethyl)- 2,3,4,5-tetrahydro-lH-1 benzodiazepine C-0 525.2 15 ,5-Difluorophenylacetyl)-L- 3-(L-Val inyl)-amino-2 3 ,5-Difluorophenylacetic C-0 557.3 valinylj-amino-2,4-dioxo-1 ,5-bis- dioxo-1 ,5-bis-(2- Acid (2-methylpropyl)-2,3 ,4,5-tetrahydro methylpropyl)-2 ,3 -1 H-i ,5-benzodiazepine tetrahydro- 1H- ___benzodiazepine________ 16 ,5-Difluorophenylacetyl)-L- 3-(L-Valinyl)-amino-2,4- 3 ,5-Difluorophenylacetic C-0 473.2 valinyll-amino-2 ,4-dioxo- 1,5-bis- dioxo- 1,5-bis-(methyl)- Acid (methyl)-2,3,4,5-tetrahydro-1H-1 ,5 2,3,4,5-tetrahydro-1H-1 _________-benzodiazepine benzodiazepine Example Compound Starting Material 1 Starting Material 2 General MS No. 17 3-IN-(3 ,5-Difluorophenylacetyl)-L- 3-(L-Valinyl)-amino-2,4- 3 ,5-Ditluorophenylacetic C-0 553.2 valinyl]-amino-2 ,4-dioxo- 1,5-bis- dioxo- 1,5-bis-(cyclopropyl- Acid (cyclopropylmethyl)-2 ,3,4 ,5-tetrahy methy l)-2 ,3,4 dro- 1H-i ,5-benzodiazepine 1 H-i ,5-benzod iazepine 18 3-IN-(3 ,5-Difluorophenylacetyl)-L- 3-(L-Norvalinyl)-amino-2 3 ,5-Ditluorophenylacetic C-0 557.3 norvalinyll-amino-2 ,4-dioxo- 1,5- dioxo-1I,5-bis-(2-methyl- Acid bis-(2-methylpropyl)-2, 3,4,5- propyl)-2 ,3 tetrahydro- 1H-i ,5-benzodiazepine 1 H-i, 5-benzodiazepine 19 3 ,5-Difluorophenylacetyl)-L- 3-(L-Norvalinyl)-amino-2 3 ,5-Difluorophenylacetic C-0 473.2 norvalinyl] -amino-2 ,4-dioxo- 1,5- dioxo- 1, 5-bis-(methyl)- Acid bis-(methyl)-2 ,3 ,4,5-tetrahydro- I H- 2,3 ,4,5-tetrahydro- I H-i I ,5-benzodiazepine benzodiazepine____ 8C-520 ,5-Difluoroplhenylacetyl)-L- 3-(L-Norvalinyl)-amino-2,4- 3 ,5-Difluorophenylacetic C-0 norvalinyl]-amino-2,4-dioxo- 1,5- dioxo- 1,5-bis-(cyclopropyl- Acid bis-(cyclopropylmethyl)-2 ,3,4 methyl)-2 ,3 ydro H-I ,5-benzodiazepine I H-i 8C-52 1 ,5-Difluorophenylacetyl)-L- 3-(L-Methioninyl)-amino-2 3 ,5-Difluorophenylacetic C-0 587.3 methioninyll-amino-2 ,4-dioxo- 1,5- dioxo- 1,5-bis-(2-methyl- Acid bis-(2-methylpropyl)-2,3 propyl)-2 ,3 tetrahydro- 1H-i ,5-benzodiazepine 1 H-i ,5-benzodiazepine 8C-522 ,5-Difluorophenylacetyl)-L- 3-(L-Methioninyl)-amino-2 3 ,5-Difluorophenylacetic C-0 503.2 methioninyl]-amino-2 ,4-dioxo- 1,5- dioxo- 1,5-bis-(methyl)- Acid bis-(methyl)-2 ,3 ,4,5-tetrahydro- 1H- 2,3 ,4,5-tetrahydro- 1 H- 1 ,5-benzodiazepine 1 Example Compound Starting Material 1 Starting Material 2 General MS No. 8C-523 ,5-Ditluoroplienylacetyl)-L- 3-(L-Methioninyl)-arnino-2,4- 3 ,5-Difluorophenylacetic C-0 583.2 methioninyll-amino-2,4-dioxo- 1,5- dioxo- 1,5-bis-(cyclopropyl- Acid bis-(cyclopropylmethyl)-2 ,3 methyl)-2,3 tetrahydro-1 H-i, 5-benzod iazepine 1 H-i ,5-benzodiazepine_____ 8C-524 3-IN-(3 ,5-Difluorophenylacetyl)-L- 3-(L-Phenylalaninyl)-arnino- 3 ,5-Ditluorophenylacetic C-0 603.3 phenylalaninyll-amino-2 ,4-dioxo- 2,4-dioxo- 1,5-bis-(2-methyl- Acid 1 ,5-bis-(2-methylpropyl)-2 ,3 propyl)-2 ,3 tetrahydro- 1 H-I 1,5-benzod iazepine 1 H- 1,5- benzodiazepine 8C-525 3-IIN-(3,5-Difluorophenylacetyl)-L- 3-(L-Phenylaianinyl)-amino- 3,5-Difluorophenylacetic C-0 519.2 phenylalaninylj-amino-2,4-dioxo- 2,4-dioxo-1 ,5-bis-(methyl)- Acid 1 ,5-bis-(methyl)-2,3 2,3 ,4,5-tetrahydro- 1 Htetrahydro- 11-1-1 ,5-benzodiazepine 1 8C-526 3-IIN-(3 ,5-Difluorophenylacetyl)-L- 3-(L-Phenylalaninyl)-amino- 3 ,5-Difluorophenylacetic C-0 601.2 phenylalaninyl]-amino-2 ,4-dioxo- 2 ,4-dioxo- 1,5-bis-(cyclo- Acid I ,5-bis-(cyclopropylrnethyl)- propylmethyl)-2 ,3 2,3 ,4,5-tetrahydro-1H-1 tetrahydro-1H-1 benzodiazepine benzodiazepine 8C-527 3-IN-(3 ,5-Difluorophenylacetyl)-L- 3-(L-Phenylglycinyl)-amino- 3 ,5-Difluorophenylacetic C-0 591.3 phenylglycinylJ-amino-2 ,4-dioxo- 2 ,4-ciioxo- 1,5-bis-(2-methyl- Acid 1 ,5-bis-(2-methylpropyl)-2 propyl)-2 ,3 tetrahydro- 1H-I ,5-benzodiazepine 1 H-i ,5-benzodiazepine 8C-528 ,5-Difluorophenylacetyl)-L- 3 -(L-Pheny Iglyc inylI)-amino- 3 ,5-Difluorophenylacetic C-0 507.2 phenylglycinylj-amino-2 ,4-dioxo- 2,4-dioxo- 1,5-bis-(methyl)- Acid 1 ,5-bis-(methyl)-2,3 2,3,4 ,5-tetrahydro- 1 H- _____tetrahydro-1IH- 1,5-benzodiazepine .1 Example Compound Starting Material 1 Starting Material 2 General MS No. IProcedure 8C-529 ,5-Difluorophenylacetyl)-L- 3-(L-Phenylglycinyl)-amino- 3 ,5-Difluorophenylacetic C-0 587.2 phenylglycinylj-amino-2 ,4-dioxo- 2 ,4-dioxo- 1, 5-bis-(cyclo- Acid 1 ,5-bis-(cyclopropylmethyl)- propylmethyl)-2 ,3,4,5- 2,3,4,S-tetrahydro-1H1-1 tetrahydro-lH-1 benzodiazepine benzodiazepine_____________ 8C-530 ,5-Difluorophenylacetyl)-(2- 3-[(2-Thienyl)glycine] -amino- 3 ,5-Difluorophenylacetic C-0 597.2 thienyl)glycinej-amino-2,4-dioxo- 2,4-dioxo- 1,5-bis-(2-methyl- Acid 1 ,5-bis-(2-metliylpropyl)-2 13,4,5- propyl)-2,3 tetrahydro- 1H-i, 5-benzodiazepine 1 H-i 8C-53 1 3 ,5-Difluorophenylacetyl)-(2- 3-[2-Thienyl)glycine]-amino- 3 ,5-Difluorophenylacetic C-0 513.1 thienyl)glycinej-amino-2,4-dioxo- 2,4-dioxo- 1,5-bis-(methyl)- Acid 1 ,5-bis-(methyl)-2,3,4,5- 2,3 ,4,5-tetrahydro-1H1- ________tetrahydro- 1H-i, 5-benzodiazepine 1 ,5-benzodiazepine 8C-532 ,5-Difluorophenylacetyl)-(2- 3-II2-Thienyl)glycine] -amino- 3 ,5-Difluorophenylacetic C-0 593.2 thienyl)glycine]-amino-2,4-dioxo- 2,4-dioxo-1 ,5-bis- Acid 1 ,5-bis-(cyclopropyliniethyl)- (cyclopropylmiethlyl)- 2,3,4,5-retrahydro-1H-1 2,3,4,5-tetrahydro-IHbenzodiazepine 1 8C-533 ,5-Difluorophenyiacetyl)-(3- 3-I(3-Thienyl)giycine]-amino- 3 ,5-Difluorophenylacetic C-0 597.2 thiienyl)glycine]-amino-2 ,4-dioxo- 2 ,4-dioxo- 1, 5-bis-(2-methyl- Acid 1 ,5-bis-(2-methylpropyl)-2 ,3 propyl)-2 ,3 tetrahydro- 1H-i ,5-benzodiazepine 1 H-I ,5-benzod iazepine 8C-534 ,5-Difluorophenylacetyl)-(3- 3[+3 -Thieny I)g lycinel -amino- 3 ,5-Difluorophenylacetic C-0 513. 1 thienyl)glycinej-amino-2 ,4-dioxo- 2,4-dioxo- 1,5-bis-(methyl)- Acid 1 ,5-bis-(methyl)-2 13,4,5- 2,3,4 ,5-tetrahydro- I H- ________tetrahydro- 1H-i ,5-benzodiazepine 1 ,5-benzodiazepine Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-535 ,5-Ditluorophenylacetyl)-(3- 3-[(3-Thieiiyl)glycinel -amino- 3 ,5-Di tluorophenylacetic C-0 593.2 thienyl)glycine]-amino-2 ,4-dioxo- 2 ,4-dioxo- 1 ,5-bis-(cyclo- Acid 1 ,5-bis-(cyclopropylmethyl)- propylmethyl)-2,3,4,5- 2,3,4,5-tetrahydro- IH- 1,5- tetrahydro-iH-1 iazepine -benzod iazepine 8C-536 ,5-Difluorophenylacetyl)-L- 3-(L-Threoninyl)-amino-2 3 ,5-Difluorophenylacetic C-0 559.3 threoninyl]-amino-2 ,4-dioxo- 1,5- dioxo- 1 ,5-bis-(2-methyl- Acid bis-(2-methylpropyl)-2,3 propyl)-2 ,3 ________tetrahydro- 1 H-1, 5-benzodiazepine 1 H-i ,5-benzodiazepine 8C-537 ,5-Difluorophenylacetyl)-L- 3-(L-Threoninyl)-amino-2 3 ,5-Difluorophenylacetic C-0 475.2 threoninyl]-amino-2 ,4-dioxo- dioxo- 1,5-bis-(methyl)- Acid I ,5-bis-(methyl)-2 2,3,4 ,5-tetraliydro- I1-I- ________tetrahydro- 1H-i, 5-benzodiazepine 1, 5-benzodiazepine 8C-538 ,5-Difluoropheny Iacetyl)-L- 3-(L-Threoninyl)-amino- 3 ,5-Difluorophenylacetic C-0 555.2 threoninyl]-amino-2 ,4-dioxo- 1,5- 2 ,4-dioxo- 1, 5-bis-(cyclo- Acid bis-(cyclopropylmethyl)-2,3 propylmethyl)-2,3 tetrahydro-l1H-i ,5-benzodiazepine tetrahydro- 1H- 8C-539 ,5-Difluorophenylacetyl)-L- 3-(L-Tyrosinyl)-amino-2 3 ,5-Ditluorophenylacetic C-0 621.3 tyrosinylj-amino-2,4-dioxo- 1,5-bis- dioxo-1I,5-bis-(2-methyl- Acid (2-methylpropyl)-2 propyl)-2 ,3 tetrahydro- 1H-i ,5-benzodiazepine 1 H-i, 5-benzodiazepine 8C-540 3-IIN-(3 ,5-Difluorophenylacetyl)-L- 3-(L-Tyrosinyl)-aniino-2,4- 3 ,5-Difluorophenylacetic C-0 537.2 tyrosinyll-amino-2 ,4-dioxo- 1,5-bis- dioxo- 1, 5-bis-(methyl)- Acid (methyl)-2,3 ,4,5-tetrahydro- 1H- 2,3 ,5-benzodiazepine 1 ,5-benzodiazepine Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-54 1 ,5-Difluoroplienylacetyl)-L- 3-(L-Tyrosinyl)-amino-2,4- 3 ,5-Difluorophenylacetic C-0 617.3 tyrosinyl]-amino-2,4-dioxo- 1,5- dioxo- 1, 5-bis-(cyclopropyl- Acid bis-(cyclopropylmethyl)-2,3 methyl)-2,3 tetrahydro- 1H-i ,5-benzodiazepine -1 H-I 8C-542 3-[N-(Cyclopentylacetyl)-L- 3-(L-Alaninyl)-amino-2,4- Cyclopentylacetic Acid C-0 485.3 alaninylJ-amino-2 ,4-dioxo- 1,5-bis- dioxo- 1,5-bis-(2-methyl- (2-methylpropyl)-2 ,3,4 propyl)-2 ________tetrahydro- 1H-i ,5-benzodiazepine 1 H-i ,5-benzodiazepine 8C-543 3-[N-(Cyclopentylacetyl)-L- 3-(L-Alaninyl)-amino-2,4- Cyclopentylacetic Acid C-0 401.2 alaninyll-amino-2,4-dioxo-i,5-bis- dioxo-i (methyl)-2,3 ,4,5-tetrahydro- 1H- 2,3,4 ,5-tetrahydro- 1H- 1 ,5-benzodiazepine I 8C-544 3-[N-(Cyclopentylacetyl)-L- 3-(L-Alaninyl)-amino-2,4- Cyclopentylacetic Acid C-0 481.3 alaninyl]-amino-2 ,4-dioxo- 1 ,5-bis- dioxo- 1 (cyclopropylmethyl)-2 ,3 methyl)-2,3 ______tetrahydro- IH-I ,5-benzodiazepine 1 H-i ,5-benzodiazepine 8C-545 3-[N-(Cyclopentylacetyl)-L- 3-(L-Valinyl)-amino-2 Cyclopenty lacetic Acid C-0 513.3 valinylJ-amino-2 ,4-dioxo-1I,5-bis- dioxo- 1,5-bis-(2-methyl- (2-methylpropyl)-2 ,3 propyl)-2,3 ________tetrahydro- 1H-i ,5-benzodiazepine 1 H-i ,5-benzodiazepine 8C-546 3-[N-(Cyclopentylacetyl)-L- 3-(L-Valinyl)-amino-2,4- Cyclopentylacetic Acid C-0 429.2 valinyl]-amino-2,4-dioxo- 1,5-bis- dioxo- (methyl)-2 ,3 ,4,5-tetrahydro- 1H- 2,3 ,4,5-tetrahydro- 1H- ,5-benzodiazepine .1 ,5-benzodiazepine Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-547 3-[N-(Cyclopentylacetyl)-L- 3-(L-VaI inyl)-amino-2 Cyclopentylacetic Acid C-0 509.3 valinyl]-amino-2,4-dioxo- 1,5-bis- dioxo-1 (cyclopropylmethyl)-2 methyl)-2 ,3,4 etrahydro- IH-I ,5-benzodiazepine 1 H-i 8C-548 3-[N-(Cyclopentylacetyl)-L- 3-(L-Norvalinyl)-amino-2 Cyclopentylacetic Acid C-0 513.3 norvalinyl]-amino-2,4-dioxo- 1,5- dioxo-1I,5-bis-(2-methylbis-(2-methy Ipropyl)-2 propyl)-2 ________tetrahydro- 1H-i ,5-benzodiazepine 1 H-i ,5-benzodiazepine 8C-549 3-[N-(Cyclopentylacetyl)-L- 3-(L-Norvalinyl)-amino-2 Cyclopentylacetic Acid C-0 429.2 norvalinyl] -amino-2 ,4-dioxo- 1,5- dioxo- 1, bis-(methyl)-2,3 ,4,5-tetrahydro- 1H- 2,3 ,4,5-tetrahydro- 1H- 1 ,5-benzodiazepine 1 ,5-benzodiazepine 8C-550 3-[N-(Cyclopentylacetyl)-L- 3-(L-Norvalinyl)-amino-2 Cyclopentylacetic Acid C-0O0 norvalinyl]-amino-2 ,4-dioxo- 1,5- dioxo- bis-(cyclopropylmethyl)-2 ,3 methyl)-2 ,3 tetrahydro- 1H-I ,5-benzodiazepine 1 H-I ,5-benzodiazepine 8C-551 8C-552 3 -[N-(Cyclopentylacetyl)-Lmethioninyl]-amino-2,4-dioxo-1 ,5bis-(2-methylpropyl)-2,3 ,4,5- (etrahydro-1H-1 ,5-benzodiazepine 3-IIN-(Cyclopentylacetyl)-Lmethioninyl] -amino-2 ,4-dioxo- 1,5bis-(methyl)-2,3 ,4,5-tetrahydro- 1H- 1 ,5-benzodiazepine 3-(L-Methioninyl)-amino-2 ,4dioxo-1 ,5-bis-(2-methylpropyl)-2, 3,4,5-tetrahydro- 1 H-i 3-(L-Methioninyl)-aniino-2 ,4dioxo-1 2,3 ,4,5-tetrahydro-1H- 1 ,5-benzodiazepine Cyclopentylacetic Acid C-0 545.3 Cyclopentylacetic Acid C-0 461.2
I
Example Compound Starting Material 1 Starting Material 2 General MS No. IProcedure 8C-553 3-[N-(Cyclopentylacetyl)-L- 3-(L-Methioninyl)-amino-2,4- Cyclopentylacetic Acid C-0 541.3 methioninylj-amino-2 ,4-dioxo- 1,5- dioxo- 1 bis-(cyclopropylmethyl)-2 methyl)-2,3 tetrahydro- 1H-i ,5-benzodiazepine 1H-i ,5-benzodiazepine 8C-554 3-[N-(Cyclopentylacetyl)-L- 3-(L-Phenylalaninyl)-arnino- Cyclopentylacetic Acid C-0 561.3 phenylalaninylJ-amino-2 ,4-dioxo- 2 ,4-dioxo- 1, 5-bis-(2-methyl- 1 ,5-bis-(2-methylpropyl)-2 propyl)-2 tetrahydro- 1H-i ,5-benzodiazepine 1 H-i ,5-benzodiazepine 8C-555 3-[N-(Cyclopentylacetyl)-L- 3-(L-Phenylalaninyl)-amino- Cyclopentylacetic Acid C-0 477.2 phenylalaninyl]-amino-2 ,4-dioxo- 2 ,4-dioxo- 1 ,5-bis-(methyl)-2 ,3 2,3 ,4,5-tetrahydro- 1 Htetrahydro- 1 H-i1, 5-benzodiazepine 1 ,5-benzodiazepine 8C-556 3-[N-(Cyclopentylacetyl)-L- 3-(L-Phenylalaninyl)-amino- Cyclopenty ]acetic Acid C-0 557.3 phenylalaninyl]-amino-2 ,4-dioxo- 2,4-dioxo- 1 ,5-bis-(cyclopropylmethyl)- propyimethyl)-2 ,3,4,5- 2,3,4,5-tetrahydro-iH-i tetrahydro-1H-i ________benzodiazepine benzodiazepine 8C-557 3-[N-(Cyclopentylacetyl)-L- 3 -(L-PhenylglycinylI)-amino- Cyclopentylacetic Acid C-0 547.3 phenylglycinylj-amino-2,4-dioxo- 2,4-dioxo-1 ,5-bis-(2- 1 ,5-bis-(2-methylpropyl)-2 methylpropyl)-2 ,3,4,5tetrahydro- 1H-i ,5-benzodiazepine tetrahydro- 1H- benzodiazepine 8C-55 8 3-[N-(Cyclopentylacetyl)-L- 3-(L-Phenylglycinyl)-amino- Cyclopenty lacetic Acid C-0 463.2 phenylglycinylj-amino-2 ,4-dioxo- 2,4-dioxo- 1 ,5-bis-(methyl)-2 ,3 2,3 ,4,5-tetrahydro- 1 H- ________tetrahydro- 1H-i, 5-benzodiazepine 1, 5-benzodiazepine 0Q Example Compound Starting Material 1 Starting Material 2 General MS No. 8C-559 3-[N-(Cyclopentylacetyl)-L- 3-(L-Pheny Iglycinyl)-amino- Cyclopentylacetic Acid C-0 543.3 phenylglycinyl]-amino-2 ,4-dioxo- 2,4-dioxo- I ,5-bis-(cyclopropylmethyl)- propylmethyl)-2 ,3,4,5- 2,3 ,4,5-tetrahydro- 1H- 1,5- tetrahydro- 1H- benzodiazepine benzodiazepine 8C-560 3-[N-(Cyclopentylacetyl)-(2- 3-[(2-Thienyl)glyc ine] -amino- Cyclopentylacetic Acid C-0 551.3 thienyl)glycine]-amino-2 ,4-d joxo- 2 ,4-dioxo- 1, 5-bis-(2-methyl- 1 ,5-bis-(2-methylpropyl)-2,3 propyl)-2,3 tetrahydro- 1H-i, 5-benzodiazepine 1 H-i 8C-56 1 3- [N-(Cyclopentylacetyl)-(2- 3 -[(2-Thienyl)glyc ine] -amino- Cyclopentylacetic Acid C-0 469.2 thienyl)glycine]-amino-2 ,4-dioxo- 2 ,4-dioxo- 1 ,5-bis-(methyl)-2,3 2,3 ,4,5-tetraliydro- I 1tetrahydro- 1H-i, 5-benzodiazepine 1 ,5-benzodiazepine 8C-562 3- [N-(Cyclopentylacetyl)-(2- 3 -[(2-ThienylI)glycine] -amino- Cyclopentylacetic Acid C-0 549.2 thienyl)glycine]-amino-2,4-dioxo- 2 ,4-dioxo- I ,5-bis-(cyclopropylmethyl)- propylmethyl)-2,3,4,5- 2,3 ,4,5-tetrahydro-1 H-i,5- tetrahydro- 1H- benzodiazepine benzodiazepine____________ 8C-563 3-[N-(Cyclopentylacetyl)-(3- 3+[3 -Thienyl)glycinel -amino- Cyclopeinylacetic Acid C-0 553.3 thienyl)glycine]-amino-2,4-dioxo- 2,4-dioxo- 1 ,5-bis-(2-methyl- 1 ,5-bis-(2-methylpropyi)-2 ,3 propyl)-2 ,3 ________tetraliydro- 1 H-i ,5-benzodiazepine 1 H-i ,5-benzodiazepine 8C-564 3 -[N-(Cyclopentylacetyl)-(3- 3-II3-Thienyl)glycine] -amino- Cyclopentylacetic Acid C-0 469.2 thiienyl)glycinel-amino-2 ,4-dioxo- 2 ,4-dioxo- 1 ,5-bis-(methyl)-2,3 2,3 ,4,5-tetrahydro- 1H-* ________tetrahydro- 1H-i ,5-benzodiazepine 1 ,5-benzodiazepine
C,
'C
'C
Example Compound Starting Material 1 Starting Material 2 General MS No. iProcedure 8C-565 3-[N-(Cyclopentylacetyl)-(3- 3-I(3-Thienyl)glycinel-amino- Cyclopentylacetic Acid C-0 549.2 thienyl)glycine]-amino-2,4-dioxo- 2 ,4-dioxo- 1, 1 ,5-bis-(cyclopropylmethyl)- propylmethyl)-2,3,4,5- 2,3,4,5-tetrahydro-LH-1,5- benzodiazepine benzodiazepine 8C-566 3-[N-(Cyclopentylacetyl)-L- 3-(L-Serinyl)-amino-2 Cyclopentylacetic Acid C-0 417.2 serinyl]-amino-2 ,4-dioxo-1 ,5-bis- dioxo- 1,5-bis-(2-methyl- (2-methylpropyl)-2 propyl)-2,3,4, ________tetrahydro- 1H-i ,5-benzodiazepine 1 H-i 8C-567 3-[N-(Cyclopentylacetyl)-L- 3-(L-Threoninyl)-amino-2 Cyclopentylacetic Acid C-0 515.3 threoninylJ-amino-2 ,4-dioxo- 1,5- dioxo- 1,5-bis-(2-methylbis-(2-methylpropyl)-2 propyl)-2 ,3,4 tetrahydro-1 H-i ,5-benzodiazepine 1 H-i, 8C-568 3-[N-(Cyclopentylacetyl)-L- 3-(L-Threoninyl)-amino-2,4-dio Cyclopentylacetic Acid C-0 431.2 threoninyl]-amino-2,4-dioxo- 1,5- xo-1 ,5-bis-(methyl)-2 ,3 bis-(methyl)-2 ,3 ,4,5-tetrahydro- ahydro- IH-i 11,5-benzodiazepine_____ 8C-569 3-IIN-(Cyclopentylacetyl)-L- 3-(L-Thireoniinyl)-amino-2,4-dio Cyclopentylacetic Acid C-0 511.3 threoninyl]-amino-2 ,4-d ioxo- 1,5- xo- 1, bis-(cyclopropylmethyl)-2,3 2,3 ,4,5-tetrahydro-1H-1 tetrahydro- 1H-i, 5-benzodiazepine 8C-570 3-IIN-(Cyclopentylacetyl)-L- 3-(L-Tyrosinyl)-amino-2 Cyclopentylacetic Acid C-0 577.3 tyrosinyl]-amino-2 ,4-dioxo- 1,5-bis- dioxo- 1 ,5-bis-(2-methyl- (2-methylpropyl)-2 propyl)-2 ,3 ________tetrahydro- 1H-i ,5-benzodiazepine 1 H-i Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-57 1 3-[N-(Cyclopentylacetyl)-L- 3-(L-Tyrosinyl)-amino-2 Cyclopentylacetic Acid C-0 493.2 tyrosinyl]-amino-2 ,4-dioxo- 1,5- dioxo- 1 bis-(methyl)-2,3 ,4,5-tetrahydro- 2,3 ,4,5-tetrahydro- 1 H- 1H-i ,5-benzod iazepine 8C-572 3-[N-(Cyclopentylacetyl)-L- 3 -(L-Tyrosinyl)-amino-2 Cyclopentylacetic Acid C-0 573.3 tyrosinyl]-amino-2 ,4-dioxo- 1,5- dioxo- 1, bis-(cyclopropylmethyl)-2,3 methyl)-2 ,3 tetrahydro- 1H-I ,5-benzodiazepine 1 H-i 8C-573 3 ,4 ,4-Trifluorobutryl)-L- .3-(L-Alaninyl)-amino-2 4,4 ,4-Trifluorobutyric Acid C-0 499.2 alaninyll-amino-2 ,4-dioxo- 1, 5-bis- dioxo- 1,5-bis-(2-methyl- (2-methylpropyl)-2 ,3 propyl)-2 ,3 ________tetrahydro- 1H-i ,5-benzodiazepine 1 H-i, 5-benzodiazepine 8C-574 ,4 ,4-Trifluorobutryl)-L- 3-(L-Alaninyl)-amino-2 4,4 ,4-Trifluorobutyric Acid C-0 415.1 alaninyl]-amino-2 ,4-dioxo- 1,5- dioxo- bis-(methyl)-2,3 ,4,5-tetrahydro- 2,3 ,4,5-tetrahydro- 1H- 11-1, 5-benzodiazepine benzodiazepine 8C-575 ,4 ,4-Tritluorobutryl)-L- 3-(L-Alaninyl)-amino-2 4 ,4,4-Trifluorobutyric Acid C-0 495.2 alaninyl]-amino-2,4-dioxo- 1,5-bis- dioxo-i (cyclopropylmethyl)-2 methyl)-2 ,3 ________tetrahydro- 1H-i ,5-benzodiazepine I H-i ,5-benzodiazepine 8C-576 3-[N-(4,4,4-Trifluorobutryl)-L- 3-(L-Valinyl)-amino-2,4- 4,4,4-Trifluorobutyric Acid C-0 527.3 val inyl] -amino-2 ,4-dioxo- 1, 5-bis- dioxo- 1,5-bis-(2-methyl- (2-methylpropyl)-2 propyl)-2 ,3 tetrahydro-1H-1 ,5-benzodiazepine 1Hl-1 ,5-benzodiazepine Example Compound Starting Material 1 Starting Material 2 General MIS No. Procedure 8C-577 ,4-Tritluorobutryl)-L- 3-(L-Val inyl)-amino-2 4 A ,4-Trifluorobutyric Acid C-0 443.2 valinylj-amino-2 ,4-dioxo-1I,5-bis- dioxo- -(methyl)-2 ,3 ,4,5-tetrahydro- 1 H- 2,3 ,4,5-tetrahydro- 1 H- 1 ,5-benzodiazepine_ benzodiazepine___ 8C-578 3-jN-(4 ,4,4-Trifluorobutryl)-L- 3-(L-Valinyl)-ainino-2 4 ,4,4-Trifluorobutyric Acid C-0 523.2 valinyll-amino-2 ,4-dioxo- 1,5-bis- dioxo- (cyclopropylmethyl)-2 ,3,4 methyl)-2 ,3 ___tetrahydro- 11-1 ,5-benzodiazepine 1 H-i ,5-benzodiazepine 8C-579 ,4 ,4-Trifluorobutryl)-L- 3-(L-Norvalinyl)-amino-2 4,4 ,4-Trifluorobutyric Acid C-0 527.3 norvalinyll-amino-2 ,4-dioxo- 1,5- dioxo- 1,5-bis-(2-methylbis-(2-methylpropyl)-2 ,3 propyl)-2,3 tetrahydro- 1H-i ,5-benzodiazepine 111-1 ,5-benzodiazepine 8C-580 3-[N-(4,4,4-Trifluorobutryl)-L- 3-(L-Norvalinyl)-amino-2,4- 4,4,4-Trifluorobutyric Acid C-0 4.
norvalinyi]-amino-2 ,4-dioxo- 1,5- dioxo- bis-(methyl)-2 ,3 ,4,5-tetrahydro- 2,3 ,4,5-tetrahydro- 1 H- 1 H-i ,5-benzodiazepine 1, 5-benzodiazepine 8C-58 1 3-[N-(4,4,4-Trifluorobutryl)-L- 3-(L-Norvalinyl)-amino-2,4- 4,4,4-Trifluorobutyric Acid C-0 523.2 norvalinyl]-amino-2,4-dioxo- 1,5- dioxo- bis-(cyclopropylmethyl)-2 methyl)-2 ,3 tetrahydro- 1H-i ,5-benzodiazepine I H-I ,5-benzodiazepine 8C-582 3-IN-(4,4,4-Trifluorobutryl)-L- 3-(L-Methioninyl)-amino-2,4- 4,4,4-Trifluorobutyric Acid C-0 559.2 methioninylJ-amino-2,4-dioxo- 1,5- dioxo- 1,5-bis-(2-methylpropyl)bis-(2-methylpropyl)-2 ,3 2,3,4 ,5-tetrahydro- 1Htetrahydro- 1H-i ,5-benzodiazepine 1, 5-benzod jazepine Example Compound Starting Material 1 Starting Material 2 General MS No. IProcedure 8C-583 ,4 ,4-Trifluorobutryl)-L- 3-(L-Methioninyl)-amino-2 4,4 ,4-Trifluorobutyric Acid C-0 475.1 methioninyll-amino-2 ,4-dioxo-1 dioxo- bis-(methyl)-2 ,3 ,4,5-tetrahydro- 2,3 ,4,5-tetrahydro-1 H-i 1H-i ,5-benzodiazepine benzodiazepine_______________ 84 ,4 ,4-Trifluorobutryl)-L- 3-(L-Methioninyl)-amino-2 4,4 ,4-Trifluorobutyric Acid C-0 555.2 methioninyl]-amino-2,4-dioxo- 1,5- dioxo-i bis-(cyclopropylmethyl)-2,3 ,4 methyl)-2,3 ________tetrahydro- 1H-i ,5-benzodiazepine 1 H-i ,5-benzodiazepine 8C-585 ,4-Trifluorobutryl)-L- 3-(L-Phenylalaninyl)-amino- 4,4 ,4-Trifluorobutyric Acid C-0 475.3 phenylalaninyl] -amino-2,4-d ioxo- 2 ,4-dioxo- 1, 5-bis-(2-methyl- 1 ,5-bis-(2-methylpropyl)-2 ,3 propyl)-2, 3,4,5-tetrahydro- ______tetrahydro- IH-i, 5-benzod iazepine 1 H-I ,5-benzodiazepine__ 8C-586 ,4 ,4-Trifluorobutryl)-L- 3-(L-Phenylalaninyl)-amino- 4,4 ,4-Trifluorobutyric Acid C-0 491.2 phenylaianinyl]-amino-2 ,4-dioxo- 2,4-dioxo-1 I ,5-bis-(methyl)-2,3,4,5- 2,3,4,5-tetrahydro-1H-1,5tetrahiydro- 1H-i, 5-benzod iazepine 8C-587 ,4 ,4-Trifluorobutryl)-L- 3-(L-Phenylalaninyl)-amino- 4,4,4-Trifluorobutyric Acid C-0 571.2 phenylalaninyl] -amino-2 ,4-dioxo- 2 ,4-dioxo- 1, 1 ,5-bis-(cyclopropylmethyl)- propylmethyl)-2,3,4,5- 2,3 ,4,5-tetrahydro- 1H-i,5- tetrahydro- 1H-i benzodiazepine, benzodiazepine 8C-588 3-[N-(4,4,4-Trifluorobutryl)- 3-(Phenylglycinyl)-amino- 4,4,4-Trifluorobutyric Acid; C-0 561.2 phenylglycinyl]-amino-2 ,4-dioxo- 2 ,4-dioxo-1 ,5-bis-(2- -1 ,5-bis-(2-methylpropyl)-2,3 methylpropyl)-2,3 tetrahydro- I H-I 1,5-benzod iazepine tetrahydro- 1H- Ibenzodiazepine.____________ Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 8C-589 3-IIN-(4 ,4,4-Trifluorobutryl)-L- 3-(L-Phenylglycinyl)-amino- 4 ,4,4-Trifluorobutyric Acid C-0 477.1 phenylglycinyl]-amino-2 ,4-dioxo- 2 ,4-dioxo- 1 1 ,5-bis-(methyl)-2,3,4,5- 2,3,4,5-tetrahydro-1H-1 tetrahydro- 1H-I, 5-benizod iazepine benzodiazepine 8C-590 3-[N-(4,4,4-Trifluorobutryl)-L- 3-[L-(2-Thienyl)giycine]- 4,4,4-Tritluorobutyric Acid C-0 567.2 (2-thienyl)glycine]-amino-2,4- amino-2,4-dioxo-1 dioxo- 1,5-bis-(2-methylpropyl)- (2-methylpropyl)-2 ,3 2,3,4 ,5-tetrahydro- 1H- 1,5- tetrahydro- 1H- _______benzodiazepine benzodiazepine 8C-59 1 3-[N-(4,4,4-Trifluorobutryl)-L- 3-[L-(2-Thienyl)glycine]- 4,4,4-Trifluorobutyric Acid C-0 483.1 (2-thienyl)glycine]-amino-2,4- amino-2,4-dioxo- dioxo-1I,5-bis-(methyl)-2 ,3 (methyl)-2 ,3 Stetrahydro- 1H-1 ,5-benzodiazepine H-,5-benzodiazepine- 8C-592 ,4-Tritluorobutryl)-L- 3-IIL-(2-Tliienyl)glycinej- 4 ,4,4-Trifluorobutyric Acid C-0 563.2 (2-thienyl)glycine]-amino-2 amino-2 ,4-dioxo- 1,5 -his- (cyclopropylmethyl)-2 ,3 2,3,4,5-tetraliydro-IH-1,5- tetrahydro-1H-1,5benzodiazepine benzodiazepine___________ 8C-593 ,4-Trifluorobutryl)-L- 3-[L-(3-Thienyl)glycine]- 4,4,4-Trifluorobutyric Acid C-0 567.2 (3-thienyl)glycine]-amino-2,4- amino-2 ,4-dioxo-1I,5-bis-(2dioxo- 1,5-bis-(2-methylpropy methylpropyl)-2 ,3,4,5- 2,3,4,5-tetrahydro-1H-1 tetrahydro-1H-1,5- -benzodiazepine Example Compound Starting Material 1 Starting Material 2 General MS No. IProcedure 8C-594 3-jN-(4 ,4 ,4-Trifluorobutryl)-L- 3-jL-(3-Thienyl)glycine]- 4,4,4-Trifluorobutyric Acid C-0 483.1 (3-thienyl)glycine]-amino-2,4- amino-2,4-dioxo-1 dioxo- 1,5-bis-(methyl)-2,3 (methyl)-2,3 tetrahydro- IH-i ,5-benzodiazepine 1 H-I ,5-benzodiazepine 8C-595 ,4,4-Trifluorobutryl)-L- 3-[L-(3-Thienyl)glycine]- 4 ,4,4-Trifluorobutyric Acid C-0 563.2 (3-thienyl)glycine]-amino-2 amino-2,4-dioxo- dioxo- 1, 5-bis-(cyclopropylmethyl)- (cyclopropylmethyl)-2 ,3,4,5- 2,3,4,5-tetrahydro-1H-1 tetrahydro-1H-1 ________-benzodiazepine benzodiazepine 8C-596 ,4-Trifluorobutryl)-L- 3-(L-Cyclohexylglycinyl)- 4,4 ,4-Trifluorobutyric Acid C-0 567.3 cyclohexylglycinyl]-amino-2,4- amino-2,4-dioxo-1 ,5-bis-(2dioxo- 1,5-bis-(2-methylpropyl)- methylpropyl)-2 ,3 2,3,4,5-tetrahydro-1H-1 tetrahydro-1H-1 benzodiazepine 8C-597 3-[N-(4,4,4-Trifluorobutryl)-L- 3-(L-Cyclohexylglycinyl)- 4,4,4-Trifluorobutyric Acid C-0 483.2 cyclohexylglycinyl]-amino-2 arnino-2 ,4-dioxo- -dioxo-1I,5-bis-(methyl)-2, 3,4,5- (inethyl)-2 ,3 .tetrahydro- 1H-i ,5-benzodiazepine I- 1111,5-benzodiazepine 8C-598 3-IIN-(4,4,4-Trifluorobutryl)-L- 3-(L-Cyclohexylglycinyl)- 4,4,4-Trifluorobutyric Acid C-0 563.3 cyclohexylglycinyl]-amino-2,4- amino-2 ,4-dioxo- 1 dioxo- 1 ,5-bis-(cyclopropylmethyl)- (cyclopropylimethyl)-2,3 2,3,4,5-tetrahydro- 1H- 1,5- tetrahydro-IH-1 benzodiazepine benzodiazepine .1 Example Compound Starting Material I Starting Material 2 General MS No. Procedure 8C-599 3-IIN-(4,4 ,4-Trifluorobutryl)-L- 3-(L-Cyclohexylglycinyl)- 4,4,4-Trifluorobutyric'Acid C-0 527.3 threoninylj-amino-2,4-dioxo-1,5- amino-2,4-dioxo- 1 bis-(2-methylpropyl)-2, 3,4,5- (2-methylpropyl)-2,3 tetrahydro- I H-i ,5-benzodiazepine tetrahydro-1 benzodiazepine 8C-600 3-IIN-(4 ,4 ,4-Trifluorobutryl)- 3-(L-Cyclohexylglycinyl)- 4 ,4,4-Trifluorobutyric Acid C-0 445 .2 threoninyll-amino-2 ,4-dioxo- 1,5- amino-2,4-dioxo- bis-(methyl)-2,3 ,4,5-tetrahydro- (methyl)-2 ,3 ,4 IH- 1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-60 1 ,4 ,4-Trifluorobutryl)-L- 3-(L-Cyclohexylglycinyl)- 4,4 ,4-Trifluorobutyric Acid C-0 525.2 threoninyll-amino-2 ,4-dioxo- 1,5- amino-2 ,4-dioxo- bis-(cyclopropylmethyl)-2,3 (cyclopropylmethyl)-2,3 t tetrahydro- 1H-i ,5-benzodiazepine tetrahydro-l1H- 1,5- 4 benzodiazepine WO 98/28268 PCTUS97/22986 555 GENERAL PROCEDURE C-P A solution of the carboxylic acid (0.75 mL, 0.05 M in DCM) was reacted with L-alaninyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (0.75 mL, 0.06 M in DCM) (from Example PP-HOBT (0.3 mL, 0.15 M in DMF, this reagent was used only with alpha substituted carboxylic acids), and EDC (0.3 mL, 0.15 The reaction was mixed for 18 hours, then purified on a Varian SCX column (500 mg column prewashed with MeOH (3 x mL) and 20% MeOH:DCM (3 x 2.5 mL)) eluting with 2.5 mL of MeOH:DCM.
GENERAL PROCEDURE C-Q Step A: FMOC-Gly Wang resin (20 g, 10.8 mmole, Novabiochem A16415) was reacted with a 30% solution of piperidine in Nmethylpyrrolidinone (NMP) for 30 minutes. The solution was drained and the resin washed with NMP (5 x 200 mL). Benzophenone imine (19.5 g, 108 mmole) in NMP (150 mL) was added to the resin followed by glacial acetic acid (5.6 g, 94 mmole) and the reaction was mixed overnight at room temperature. Reagents were drained and the resin washed with NMP (5 x 150 mL) followed by DCM (5 x 150 mL). The resin was dried under vacuum to afford (benzophenone imine)-Gly Wang resin with a theoretical loading of 0.56 mmole per gram.
Step B: A suspension of the resin from Step A in NMP (9 mL) was reacted with an alkyl bromide (5.6 mL of 1 M solution in NMP) selected from 1-bromo-2-ethylbutane, 1-bromo-3-methylbutane, cyclopropylmethyl bromide, 1-bromo-2-cyclohexylethane, 1-bromo-4-fluorobutane, and 1-bromo-2methylbutane; and BEMP (5.6 mL of 1 M solution in NMP) and Bu 4 NI (5.6 mL of 1 M solution in NMP) for 20 hours at room temperature. Reagents were drained and the resin washed with NMP (3 x 15 mL). To a mixture of the resin in THF (7 mL) was added hydroxylamine hydrochloride (2 mL of a 1.6 M solution in water) and the reaction was mixed for 20 hours at room WO 98/28268 PCTIUS97/22986 556 temperature. Reagents were drained and the resin washed sequentially with THF (2 x 5 mL), 0.5 M solution of diisopropylethylamine in THF (5 mL), THF (5 mL), and NMP (3 x 5 mL).
Step C: The resin from Step B was divided into 12 equal reactions using an isopicnic solution in NMP:CH 2 C2. To each reaction was added sequentially a carboxylic acid (0.75 mL of a 0.45 M solution in NMP), HOBT (0.75 mL of a 0.45 M solution in NMP) and DIC (0.75 mL of a 0.45 M solution in NMP). The reaction was mixed for 18 hours at room temperature. Reagents were drained and the resin washed with NMP (5 x 0.5 mL), and DCM (5 x mL). The resin was mixed with TFA:H,O (95:5, 0.5 mL) for 4 hours. The filtrate was collected, resin washed with TFA:H 2 0 (95:5, 0.5 mL) and the filtrates combined. Solvents were evaporated to yield the N-acyl amino acid.
GENERAL PROCEDURE C-R Various acylated amino acids (approximately 0.02 mmole) (from General Procedure C-Q) in separate vials were reacted with 5-amino-7-methyl-5,7dihydro-6H-dibenz[bd]azepin-6-one (0.1 mL, 0.3 M in DCM) (Example 7-A), PP-HOBT (0.2 mL, 0.15 M in DMF), and EDC-HC1 (0.4 mL, 0.08 M in DCM). Reactions were mixed for 18 hours at room temperature. Reactions were diluted with 0.5 mL MeOH, loaded onto a Varian SCX column (500 mg, Varian Sample Preparations, pre-washed with MeOH (2.5 mL) and MeOH:CHCl 3 (2.5 and eluted with 10% MeOH:CHCl 3 (2.5 mL).
Solvents were evaporated from the products and the crude products purified by semi-prep reverse phase chromatography (gradient 0 to 100 0.1% TFA in H,O to 0.08% TFA in CH 3 CN). The correct molecular ion was detected for each product by ionspray mass spec and analytical reverse phase chromatography (gradient 0 to 100 0.01% TFA in H,O to 0.08% TFA in
CH
3 CN) showed the products to be greater than 90% pure.
WO 98/28268 PCT/US97/22986 557 Using the procedures indicated, the compounds shown in Table C-4 were prepared. In this table, starting material 2 was prepared as described in Example 7-I.
Table C-4 EapeCompound Starting Material I Starting Material 2 General MVS No. Procedure 7C- 1 5-{N '-(Cyclopentyl acetyl)-L- Cyclopentyl acetic acid 5-(L-alaninyl)-amino'-7- c-P 420.2 alaninyl)-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6Hdihydro-6H-dibenz[b ,dlazepin-6- dibenz[b,d]azepin-6-one one 7C-2 5- {N'-(3-cyclopentylpropionyl)-L- 3-cyclopentylpropionic 5-(L-alaninyl)-amino-7- C-P 434.2 acid methyl- 7-dihydro-6Hdihydro-6H-dibenz[b ,d]azepin-6- (Aldrich) dibenz[b,djazepin-6-one one 7C-3 5-{N'-(cyclohexylacetyl)-L- cyclohexylacetic acid 5-(L-alaninyl)-amino-7- C-P 434.2 alaninyl) -amino-7-methyl-5 (Aldrich) methyl-S ,7-dihydro-6Hdihydro-6H-dibenz[b,djazepin-6- dibenz[b, dlazepin-6-one one 7C-4 5-{N'-(t--butylacetyl)-L-alaninyl t-butylacetic acid 5-(L-alaninyl)-amino-7- C-p 408.2 ami no-7-methyl-5 ,7-dhydro-6Hl- (Aldrich) inethyl- 7-dihydro-6Hdibenz[b,d_]azepin-6-one dibenz[b ,djazepin-6-one 5-{N'-(pbenylacetyl)-L-alaninyl}- phenylacetic acid 5-(L-alaninyl)-amino-7- C-P 428.2 ,7-dihydro-6H- (Aldrich) methyl-S ,7-dihydro-6Hdibenz[b ,d]azepin-6-one dibenz[b,djazepin-6-one -Inm Example Compound Starting Material 1Starting Material 2 General MS No. Procedure 7C-6 5- -(3-bromnoplhenylacetyl)-L- 3-bromophenylacetic acid 5 -(L-alaninyl)-amino-7- C-P 506.0, alaninyI) -amino-7-methyl-5 (Aldrich) methyl-S ,7-dihydro-6H- 508.0 dihydro-6H-dibenz[b,dlazepin-6- dibenzib ,dlazepin-6-one one 7C-7 5-{N'-(3-fluorophenylacetyl)-L- 3-fluorophenylacetic acid 5-(L-alaninyl)-amnino-7- C-P 446.0 (Aldrich) methyl-S ,7-dihydro-6Hdihydro-6H-dibenzfb,d]azepin-6- dibenz[b azepin-6-one 7C-8 -(3-chlorophenylacetyl)-L- 3-chlorophenylacetic acid 5-(L-alaninyl)-amino-7- C-P 462.2 alaninyl) -Amino-7-methyl-5 (Aldrich) methyl-S ,7-dihydro-6Hdihydro-6H-dibenz[b azepin-6- dibenz[b ,djazepin-6-one one 7C-9 3- 5-(L-alaninyl)-amino-7- C-P 496.0 (trifluoromethyl)phenylacetyl)-L- (trifluoromethyl)phenylace methyl-S ,7-dihydro-6Halaninyl }-amino-7-methyl-5 tic acid dibenz[b ,d]azepin-6-one dihydro-6H-dibenz[b,djazepin-6- (Marshailton) one 7C- 10 5-{N'-(4-fluorophenylacetyl)-L- 4-fluorophenylacetic acid 5-(L-alaninyl)-amino-7- C-P 446.0 alaniny I -amino-7-methyl-5 (Aldrich) methyl-S ,7-dihydro-6Hdihydro-6H-dibenz[b,d]azepin-6- dibenz[b,djazepin-6-one one 7C-1 1 5-{N'-(hexanoyl)-L-alaninyl}- hexanoic acid 5-(L-alaninyl)-amino-7- C-P ,7-dihydro-6H- (Aldrich) methyl-S ,7-dihydro-6Hdibenz[b ,dlazepin-6-one dibenz[b,d]azppin-6-one Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 7C-12 N' -(heptanoyl)-L-alaninyl heptanoic acid 5-(L-alaninyl)-amino-7- C-P 422.2 ,7-dihydro-6H1- (Aldrich) methyl-S ,7-dihydro-6Hdibenz[b,djazepin-6-one dibenzlb,dlazepin-6-one 7C- 13 5-{3 ,4-difluorophenylacetyl)-L- 3 ,4-difluorophenylacetic 5-(L-alaninyl)-amino-7- C-P 464.2 alaninyl}-amino-7-methyl-S acid methyl-S ,7-dihydro-6Hdihydro-6H-dibenzlb ,d]azepin-6- (Aldrich) dibenz[b ,dlazepin-6-one one XC-14 5-{N '-(cyclopropylacetyl)-L- cyclopropylacetic acid 5-(L-alaninyl)-amino-7- C-P 392.2 alaninyl) -amino-7-methyl-5 (Lancaster) methyl-S ,7-dihydro-6Hdihydro-6H-dibenz[b ,djazepin-6- d ibenz[b ,d]azepin-6-one one 7C-15 -(2-cyclopentene-1 -acetyl)-L- 2-cyclopentene- 1 -acetic 5-(L-alaninyl)-amino-7- C-P 418.2 alaninyl} -amino-7-methyl-5 acid methyl- 7-d ihydro-6Hdihydro-6H-dibenzllb,djazepin-6- (Aldrich) dibenz[b ,djazepin-6-one one XC-16 -(3-cyclohexylpropionyl)-L- 3-cyclohexyipropionic acid 5-(L-alaninyl)-amino-7- C-P 448.0 (Aldrich) methyl-S. 7-dihydro-6Hd ihydro-6H-dibenz[b ,djazepin-6- dibenz[b ,djazepin-6-one one 7C-17 5-{N'-(isovaleryl)-L-alaninyl)- isovaleric acid 5-(L-alaninyl)-amino-7- C-P 39.
,7-dihydro-6H- (Aldrich) methyl-S ,7-dihydro-6Hdibenz[b ,djazepin-6-one dibenz[b,d]azepin-6-one Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure" 7C- 18 -(citronellyl)-L-alaninyl}- citronellic acid 5-(L-alaninyl)-amino-7- C-P 462.2 ,7-dihydro-6H- (Aldrich) methyl-S ,7-dihydro-6Hdibenz~b ,dlazepin-6-one dibenz[b,dlazepin-6-one 7C- 19 -(3-benzoylpropionyl)-L- 3-benzoylpropionic acid 5-(L-alaninyl)-amino-7- C-P 470.2- (Aldrich) methyl-5 ,7-dihydro-6Hdihydro-6H-dibenz[b,djazepin-6- dibenzllb,dljazepin-6-one one 7C-20 -(2-chlorophenylacetyl)-L- 2-chlorophenylacetic acid 5-(L-alaninyl)-amino-7- C-P 462.2 (Aldrich) methyl-S ,7-dihydro-6Hdiliydro-6H-dibenz[b ,dlazepin-6- dibenz[b,dlazepin-6-one one 7C-21 5-{N'-(4-pentenoyl)-L-alaninyl}- 4-pentenoic acid 5-(L-alaninyi)-amino-7- c-P 392.0 ,7-dihydro-6H- (Aldrich) me thyl1-S,7-dihyd ro-6Hdibenz[b,djazepin-6-one dibenzllb,dlazepin-6-one 7C-22 5 -{N'-(valerylI)-L-alaninyl} -arnino- valeric acid 5-(L-alaninyl)-amino-7- C-P 394.0 7-methyl-S ,7-d ihydro-6H (Eastman) methiyl-S. 7-dihydro-6Hd ibenz[b ,djazepin-6-one dibenz[b,djazepin-6-one 7C-23 5-{N'-(2-thiophenecetyl)-L- 2-thiophenecetic acid 5-(L-alaninyl)-amino-7- C-P 434.2 (Aldrich) methyl-5 ,7-dihydro-6Hdihydro-6H-dibenz[b,djazepin-6- dibenz[b,djazepin-6-one one Example Compound Starting Material 1 Starting Material 2 General Ms.
No. Procedure 7C-24 -(4-(2-thienyl)butyryl)-L- 4-(2-thienyl)butyric acid 5-(L-alanin~l)-amino-7- C-P 462.2 37- (Aldrich) mty5,7-dihydro-6Hdihydro-6H-dibenz[b ,d]azepin-6- dibenz[b,djazepin-6-one one 7C-25 N' -(4-(4-nitrophenyl)butyryl)-L- 4-(4-nitrophenyl)butyric 5-(L-alaninyl)-amino-7- C-P 501.0 alaninyl)}-amino-7-methyl acid mty5,7-dihydro-6Hdihydro-6H-dibenzllb,dlazepin-6- (Aldrich) dibenz[b ,djazepin-6-one one 7C-26 5- ,4-difluorophenylacetyl)-L- 2 ,4-difluorophenylacetic 5-(L-alaninyl)-amino-7- C-P 464.2 alaninyl} -amino-7-methyl-5 37- acid mty-,7-dihydro-6Hdihydro-6H-dibenz[b ,d]azepin-6- (Aldrich) dibenz[b ,dlazepin-6-one 7C-27 5- {N ,6-difluorophenylacetyl)-L- 2 ,6-difluorophenylacetic 5-(L-alaninyl)-amino-7- C-P 464.2 alaninyl }-amino-7-methyl-5, 7- acid methyl-S ,7-dihydro-6Hdihydro-6H-dibenz[b ,djazepin-6- (Aldrich) dibenz[b ,d]azepin-6-one one 7C-28 5 -(4-isopropylphenylacetyl)-L- 4-isopropylphenylacetic 5-(L-alaniny I)-amino-7- C-P 470.2 alaninyl) -amino-7-methyl-5 acid methyl-S ,7-dihydro-6Hd ihydro-6H-dibenzlb ,djazepin-6- (Lancaster) dibenz[b ,dlazepin-6-one one XC-29 -adamantaneacetyl)-L- 1 -adamantaneacetic acid 5-(L-alaninyl)-amino-7- C-P 486.4 7- (Aldrich) methyl-S ,7-dihydro-6Hdihydro-6H-dibenz[b,d]azepin-6- dibenz[b,dlazepin-6-one Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 7C-30 N' -(cyclohexanepentanoyl)-L- cyclohexanepentanoic acid 5-(L-alanin~l)-amino-7- c-p 476.2 alaninyl }-amino-7-methyl-5 (Aldrich) methyl- 7-dihydro-6Hd ihydro-6H-dibenz[b, dlazepin-6- dibenzllb,dlazepin-6-one one 7C-31 5-{N'-((methylthio)acetyl)-L- (methylthio)acetic acid 5-(L-alaninyl)-amino-7- C-P 398.0 alaninyl }-amino-7-methyl-5 (Aldrich) methyl-S ,7-dihydro- 6Hdihydro-6H-dibenzlb ,djazepin-6- dibenz[b ,d]azepin-6-one one 7C-32 5 '-(2-thiophenepentanoyl)-L- 2-thiophenepentanoic acid 5-(L-alaninyl)-amino-7- C-p 476.0 alaninyl) -amino-7-methyl-5 (Aldrich) methyl-5 ,7-dihydro-6Hdihydro-6H-dibenz~b ,djazepin-6- dibenz~b,djazepin-6-one one 7C-33 5- {N '-(2-norbornaneacetyl)-L- 2-norbornaneacetic acid 5-(L-alaninyl)-amino-7- C-P 446.0 alaninyl }-amino-7-methyl-5 (Aldrich) methyl-S ,7-dihydro-6Hdihydro-6H-dibenz[b ,dlazepin-6- dibenz[b ,djazepin-6-one one 7C-34 5-{N ,5-difluorophenylacetyl)-4- (3 ,5-difluorophenylacetyl)- 5-amino-7-methyl-5 C-R 534.2 ethylnorleucinyl) -amino-7-methyl- 4-ethylnorleucine dihydro-6H- 7-dihydro-6H-dibengb ,dlazepin- (General Procedure C-Q) dibenz[bd]azepin-6-one 6-one ,5-difluorophenylacetyl)-4- (3 ,5-ditluorophenylacetyl)- 5-amino-7-methyl-5 C-R 520.2 methylnorleucinyl }-amino-7- 4-methylnorleucine dihydro-6Hmethyl-S ,7-dihydro-6H- (General Procedure C-Q) dibenz[bdlazepin-6-one dibenz[b Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 7C-36 5-{N ,5-difluorophenylacetyl)-3- (3 ,5-difluorophenylacetyl)- 5-amino-7-ilnethyl-5 C-R 504.0 cyclopropylalaninyl }-amino-7- 3-cyclopropylalanine dihydro-6Hmethyl-S ,7-dihydro-6H- (General Procedure C-Q) dibenz[bdlazepin-6-one dibenz[b ,djazepin-6-one________ 7C-37 5-{N ,5-difluorophenylacetyl)-4- (3 ,5-difluorophenylacetyl)- 5-amino-7-methyl-5 C-R 560.2 cyclohexylhomoalaninyl} -amino-7- 4-cyclohexylhomoalanine dihydro-6Hmethyl-S ,7-dihydro-6H- (General Procedure C-Q) dibenz[bdlazepin-6-one dibenz[b,d]azepin-6-one 7C-38 5-{N ,5-difluorophenylacetyl)-6- (3 ,5-difluorophenylacetyl)- 5-amino-7-methyl-5 C-R 524.0 fluoronorleucinyl) -amino-7-methyl- 6-fluoronorleucine dihydro-6H- ,7-dihydro-6H-dibenz~b ,d]azepin- (General Procedure C-Q) dibenz[bdlazepin-6-one 6-one 7C-39 5-f{N' ,5-difluorophenylacetyl)-4- (3 ,5-difluorophenylacetyl)- 5-amino-7-methyl-5 C-R 520.0 methylnorleucinyl)}-amino-7- 4-methylnorleucine dihydro-6Hmethyl-S ,7-dihydro-6H- (General Procedure C-Q) dibenz[bd]azepin-6-one dibenzlb ,dlazepin-6-one__ 7C-40 -(cyclohexylacetyl)-4- (cyclohexylacetyl)-4- 5-amino-7-methyl-5 C-R 504.3 ethylnorleucinyl }-amino-7-methyl- ethy Inorleucine dihydro-6H- ,7-dihydro-6H-d ibenzllb ,diazepin- (General Procedure C-Q) dibenzbdlazepin-6-one 6-one 7C-41 -(cyclopropylacetyl)-4- (cyclopropylacetyl)-4- 5-amino-7-methyl-5 C-R 462.3 ethylnorleucinyl}-amino-7-methyl- ethylnorleucine dihydro-6H- 7-dihydro-6H-dibenzlb ,dlazepin- (General Procedure C-Q) dibenz[bdlazepin-6-one 6-one Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 7C-42 5-{N'-(isovaleryl)-4- (isovaleryl)-4- 5-amino-7-inetliyl-5,7- C-R 464.3 ethylnorleucinylj -amino-7-methyl- ethylnorleucine dihydro-6H- ,7-dihydro-6H-dibenz[b ,djazepin- (General Procedure C-Q) dibenz[bdlazepin-6-one 6-one 7C-43 5-amino-7-methyl-5,7- C-R 566.3 (trifluoromethyl)phenylacetyl)-4- (tri fluoromethyl)pheny lace dihydro-6Hethylnorleucinyl }-amino-7-methyl- tyl)-4-ethylnorleucine dibenzllbdlazepin-6-one ,7-dihydro-6H-dibenz[b,djazepin- (General Procedure C-Q) 6-one 7C-44 ,4-difluorophenylacety)-4- (3 ,4-difluorophenylacetyl)- 5-amino-7-methyl-5 C-R 534.3 ethylnorleucinyl}-amino-7-methyl- 4-ethylnorleucine dihydro-6H- 7-d ihydro-6H-dibenz[b ,diazepin- (General Procedure C-Q) d ibenzfbdlazepin-6-one 6-one 7C-45 5-{N ,4-difluorophenylacety)-4- (2 ,4-difluorophenylacetyl)- 5-amino-7-methyl-5 C-R 534.3 ethylnorleucinyl) -amino-7-methyl- 4-ethylnorleucine dihydro-611- ,7-dihydro-6H-dibenz[b,djazepin- (General Procedure C-Q) dibenzfbdlazepin-6-one 6-one 7C-46 5-{N '-(3-fluorophenylacetyl)-4- (3 -fluorophenylacetyl)-4- 5-amino-7-methyl-5 C-R 502.3 methylnorleucinyl }-amino-7- methylnorleucine dihydro-6Hmethyl-S ,7-dihydro-6H- (General Procedure C-Q) dibenz[bd]azepin-6-one dibenz[b,dlazepin-6-one I I_ I Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure XC-47 5-{N'-(cyclopentylacetyl)-4- (cyclopentylacetyl)-4- 5-amino-7-inethyl-5,7- C-R 476.3 methy lnorleucinyl} -amino-7- methylnorleucine dihydro-611- ,7-dihydro-6H- (General Procedure C-Q) dibenz[bdlazepi n-6-one dibenz[b,d]azepin-6-one___ XC-48 5-{N '-(cyclohexylacetyl)-4- (cyclohexylacetyl)-4- 5-amino-7-methyl-5 C-R 490.3 methylnorleucinyl)}-amino-7- methylnorleucine dihydro-6Hmethyl-S ,7-dihydro-6H- (General Procedure C-Q) dibenzlbdlazepin-6-one dibenz[b ,d]azepin-6-one XC-49 5-IN'-(cyclopropylacetyl)-4- (cyclopropylacetyl)-4- 5-amino-7-methyl-5 C-R 448.2 methylnorleucinyl)}-amino-7- methylnorleucine dihydro-6Hmethyl-S ,7-dihydro-6H- (General Procedure C-Q) dibenz[bd]azepin-6-one dibenz[b ,djazepin-6-one_________ 7C-50 5-{N '-(2-thiopheneacetyl)-4- (2-thiopheneacetyl)-4- 5 -amino-7-methyl-5 C-R 490.2 methylnorleucinyl)}-amino-7- methylnorleucine dihydro-6Hmethyl-S ,7-dihydro-6H- (General Procedure C-Q) dibenz[bdllazepin-6-one dibenz[b ,dlazepin-6-one 1 5N'-(isovaleryl)-4- (isovaleryi)-4- 5-amino-7-methyl-5 C-R 450.3 methylnorleucinyl)}-amino-7- methylnorleucine dihydro-6H- ,7-dihydro-6H- (General Procedure C-Q) dibenz[bd]azepin-6-one dibenz[b,djazepin-6-one____________ Example Compound Starting Material 1 Starting Material 2 General MS No. ________Procedure 7C-52 5-amino-7-inethyl-5,7- C-R 552.3 (trifluoromethyl)phenylacetyl)-4- (tritluoromethy l)pheny lace diliydro-6Hmethylnorleucinyl }-amino-7- tyl)-4-methylnorleucine dibenzllbd]azepin-6-one methyl-S ,7-dihydro-6H- (General Procedure C-Q) dibenz[b ,djazepin-6-one 7C-53 5-{N'-(4-fluorophenylacetyl)-4- (4-fluorophenylacetyl)-4- 5 -amino-7-methyl-5 C-R 502.3 methylnorleucinyl }-amino-7- methylnorleucine dihydro-6Hmethyl-S ,7-dihydro-6H- (General Procedure C-Q) dibenz[bdlazepin-6-one dibenz[b,d]azepin-6-one XC-54 5- ,4-difluorophenylacetyl)-4- (3 ,4-difluoropheny lacetyl)- 5-amino-7-methyl-5 C-R 520.2 methylnorleucinyl}-amino-7- 4-methylnorleucine dihydro-6Hmethyl-S ,7-dihydro-6H- (General Procedure C-Q) dibenzllbdlazepin-6-one dibenz[b ,d]azepin-6-one 5- ,4-difluorophenylacetyl)-4- (2 ,4-difluorophenylacetyl)- 5 -amino-7-methyl-5 C-R 520.3 methylnorleucinyl)}-amino-7- 4-methylnorleucine dilhydro-6Hmethyl-S ,7-dihydro-611- (General Procedure C-Q) dibenzllbdlazepin-6-one dibenz[b,djazepin-6-one 7C-56 5-{N '-(3-fluorophenylacetyl)-4- (3-fluorophenylacetyl)-4- 5-amino-7-methyl-5 C-R 542.3 cyclohexyihomoalaninyl)}-amino-7- cyclohexyihomoalanine dihydro-6Hmethyl- 7-dihydro-6H- (General Procedure C-Q) dibenz[bdjazepin-6-one Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 7C-57 N' -(cyclopentylacetyl)-4- (cyclopenty lacetyl)-4- 5-amino-7-iethyl-5 C-R 516.3 cyclohexylhomoalaninyl) -amino-7- cyclohexyihomoalanine dihydro-6Hmethyl-S ,7-dihydro-6H- (General Procedure C-Q) dibenz[bdJazepin-6-one dibenz[b ,dlazepin-6-one 7C-58 5-(N'-(cyclohexylacetyl)-4- (cyclohexylacetyl)-4- 5-amino-7-methyl-5 C-R 530.4 cyclohexyihomoalaninyl }-amino-7- cyclohexyihomoalanine dihydro-6Hmethyl-S ,7-dihydro-6H- (General Procedure C-Q) dibenzllbdlazepin-6-one dibenz[b,d]azepin-6-one 7C-59 5-{N '-(cyclopropylacetyl)-4- (cyclopropylacetyl)-4- 5-amino-7-methyi-5 C-R 488.3 cyclohexylhomoalaninyl} -amino-7- cyclohexylhomoalanine dihydro-6Hmethyl-S ,7-dihydro-6H- (General Procedure C-Q) dibenz[bd]azepin-6-one dibenz[b,djazepin-6-one 7C-60 5-{N'-(isovaleryl)-4- (isovaleryl)-4- 5-amino-7-methyl-5,7- C-R 490.3 cyclohexylhomoalaninyl )-amino-7- cyclohexyihomoalanine diliydro-6Hmethyl-S ,7-dihydro-6H- (General Procedure C-Q) d ibenz[bdjazepin-6-one dibenz[b ,d]azepin-6-one 7C-61I -(4-fluorophenylacetyl)-4- (4-fluorophenylacetyl)-4- 5-amino-7-methyl-5 C-R 542.3 cyclohexylhomoalaninyl}-amino-7- cyclohexyihomoalanine dihydro-6Hmethyl-S. 7-dihydro-6H- (General Procedure C-Q) d ibenzllbdjazepin-6-one dibenz[b,djazepin-6-one XC-62 ,4-difluorophenylacetyl)-4- (3 ,4-difluorophenylacetyl)- 5-amino-7-methyl-5 C-R 560.3 cyclohexylhomoalaninyl }-amino-7- 4-cyclohexylhomoalanine dihydro-6Hmethyl-S ,7-dihydro-6H- (General Procedure C-Q) dibenz[bdjazepin-6-one __dibenz[b,d]azepin-6-one I I I_ I_ Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 7C-63 5-{N ,4-difluorophenylacety (2 ,4-d ifluorophenylacetyl)- 5-arnino-7-inethl C-R 560.3 cyclohexyihomoalaninyl)}-amino-7- 4-cyclohexyihomoalanine dihydro-6H- ,7-dihydro-6H- (General Procedure C-Q) d ibenz[bdlazepin-6-one ibenz[b,d]azepin-6-one 7C-64 5{'-(3-fluorophenylacetyl)-6- (3-fluorophenylacetyl)-6- 5-amino-7-methyl-5 C-R 506.2 fluoronorleucinyl }-amino-7-methyl- fluoronorleucine dihydro-6H- ,7-dihydro-6H-dibenz[b,dJazepin- (General Procedure C-Q) dibenz[bdjazepin-6-one 6-one 7C-65 5-{N'-(cyclopentylacetyl)-6- (cyclopentylacetyl)-6- 5-amino-7-methyl-5 C-R 480.3 fluoronorleucinyl)}-amino-7-methyl- fluoronorleucine dihydro-6H- ,7-dihydro-6H-dibenz[b,djazepin- (General Procedure C-Q) dibenz[bd] azepin-6-one .6-one 7C-66 5-{N'-(cyclohexylacetyl)-6- (cyclohexylacetyl)-6- 5-amino-7-methyl-5 C-R 494.3 fluoronorleucinyl )-amino-7-methyl- fluoronorleucine dihydro-6H- 7-dihydro-6H-dibenz[b ,diazepin- (General Procedure C-Q) dibenzfbdjazepin-6-one 6-one 7C-67 5- -(cyclopropylacetyl)-6- (cyclopropylacetyl)-6- 5-amino-7-methy 1-5,7- C-R 452.2 fluoronorleucinyl} -amino-7-methyl- fluoronorleucine dihydro-6H- 5,7-dihydro-6H-dibenz[b,djazepin- (General Procedure C-Q) dibenz[bdlazepin-6-one 6-one 7C-68 5-{N '-(isovaleryl)-6- (isovaleryl)-6- 5-amino-7-methyl-5 C-R 454.2 fluoronorleucinyl} -amino-7-methy I- fluoronorleucine dihydro-6H- ,7-dihydro-6H-dibenz[b ,dlazepin- (General Procedure C-Q) dibenz[bdlazepin-6-one _6-one 1- Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 7C-69 5-amino-7-inethyl-5,7- C-R 556.2 (trifluoromethyl)phenylacetyl)-6- (tri fluoromethylI)pheny lace dihydro-6Hfluoronorleucinyl)}-amino-7-methyl- tyl)-6-fluoronorleucine dibenz[bdjazepin-6-one 7-dihydro-6H-dibenzlb ,diazepin- (General Procedure C-Q) 6-one 7C-70 5-{N'-(4-fluorophenylacetyl)-6- (4-fluorophenylacetyl)-6- 5-amino-7-methyl-5,7- C-R 506.2 fluoronorleucinyl }-amino-7-methyl- fluoronorleucine dihydro-6H- ,7-dihydro-6H-dibenzlb ,dlazepin- (General Procedure C-Q) dibenz[bd]azepin-6-one 6-one 7C-7 1 ,4-difluorophenylacetyl)-6- (3 ,4-difluorophenylacetyl)- 5-amino-7-methyl-5 C-R 524.2 fluoronorleucinyl}-amino-7-methyl- 6-fluoronorleucine dihydro-6H- ,7-dihydro-6H-dibenz[b ,d]azepin- (General Procedure C-Q) dibenzllbd]azepin-6-one 6-one 7X-72 ,4-difluorophenylacetyl)-6- (2 ,4-difluorophenylacetyl)- 5-am ino-7-methyl-5 C-R 524.2 fluoronorleucinyl)}-amino-7-methy I- 6-fluoronorleucine dihydro-6H- ,7-dihydro-6li-dibenz[b,djazepin- (General Procedure C-Q) dibeiizfbdlazepin-6-one 6-one 7C-73 5- '-(4-methoxyphenylacetyl)-L- 4-methoxyphenylacetic 5-(L-alaninyl)-amino-7- C-P 458.2 acid methyl-S. 7-dihydro-6Hdihydro-6H-dibenz[b,djazepin-6- (Aldrich) dibenz[b ,djazepin-6-one one Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 7C-74 5-(L-alanin~l)-amino-7- C-P 472.2 methoxyphenyl)propionyl)-L- methoxyphenyl)propionic methyl-5 ,7-dihydro-6Halaninyl) -amino-7-methyl-5 acid dibenz[b ,djazepin-6-one dihydro-6H-dibenz[b,djazepin-6- (Aldrich) one 7C-75 -naphthylacetyl)-L- 1-naphthylacetic acid 5-(L-alaninyl)-amino-7- C-P 478.2 (Aldrich) methyl-S ,7-dihydro-6Hdihydro-6H-dibenz[b,djazepin-6- dibenz[b ,djazepin-6-one one 7C-76 3,4- 5-(L-alaninyl)-amino-7- C-P 472.2 methy lenedioxyphenylacetyl)-L- methylenedioxyphenylaceti methyl-5,7-dihydro-6Hc acid dibenz[b,dlazepin-6-one d ihydro-6H-dibenz[b, d]azepin-6- (Aldrich) one 7C-77 5 -(hydrocinnamyl)-L- hydrocinnamic acid 5-(L-alaninyl)-amino-7- C-P 442.2 (Aldrich) methyl-S ,7-dihydro-6Hdihiydro-6Hi-dibenz[b,djazepin-6- d ibenzfb ,dlazepin-6-one one XC-78 5-{N'-(octanoyl)-L-alaninyl}- octanoic acid 5-(L-alaninyl)-amino-7- C-P 436.2 ,7-dihydro-6H- (Aldrich) methyl-S ,7-dihydro-6Hdibenz[b,djazepin-6-one dibenz[b ,djazepin-6-one Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 7C-79 3(-5-(L-alanin))l)-amino-7- C-p 458.2 hydroxyphenyl)propionyl)-L- hydroxyphenyl)propionic mnethyl- 7-dihydro-6Hacid dibenz[b ,d]azepin-6-one dihydro-6H-dibenzjb ,d]azepin-6- (Lancaster) one 7C-80 5-(L-alaninyl)-amino-7- c-P 456.2 methylphenyl)propionyl)-L- methylphenyl)propionic methyl-S ,7-dihydro-6Halaninyl} -amino-7-methyl-5 acid d ibenz[b ,djazepin-6-one dihydro-6H-dibenzgb,d]azepin-6- (Lancaster) one 7C-81 5-(L-alaninyl)-amino-7- C-P 476.1, chlorophenyl)propionyl)-L- chlorophenyl))prop ionic methyl-S ,7-dihydro-6H- 478.1 acid dibenz[b ,dlazepin-6-one dihydro-6H-dibenz[b ,djazepin-6- (Trans World) one 7C-82 5-{N'-(3-phenylbutyryl)-L- 3-phenylbutyric acid 5-(L-alaninyl)-amino-7- C-P 456.2 (Aldrich) methyl-S ,7-dihydro-6Hdihydro-6H-dibenz[b ,djazepin-6- dibenz[b ,dlazepin-6-one XC-83 5-(L-alaninyl)-amino-7- C-P 458.2 hydroxyphenyl)propiony hydroxyplienyl)propionic methyl-S ,7-dihydro-6Hacid dibenz[b ,djazepin-6-one dihydro-6F1-dibenzllb,d]azepin-6- (Aldrich)
IIL
Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 7C-84 ,4,5-trifluorophenylacetyl)- 3 ,4,5-trifluorophenylacetic 5-(L-alaninjl)-amino-7- C-P 482.1 L-alaninyl)-amino-7-methyl-5,7- acid methyl-5,7-dihydro-6Hdihydro-6H-d ibenz[b ,dlazepin-6- (Fiuorochem) d ibenzlb ,dlazepin-6-one one 7C-85 5-(L-alaninyl)-amino-7- C-P 486.2 methoxyphenyl)butyryl)-L- methoxyphenyl)butyric methyl-S ,7-dihydro-6Halaninyl) -amino-7-methyl-5 acid dibenz[b,djazepin-6-one dihydro-6H-dibenzlb ,dlazepin-6- (Aldrich) one 7C-86 mono-methyl succinate 5-(L-alaninyl)-amino-7- C-P 424.1 (Methoxycarbonyl)propionyl)-L- 3- methyl-S ,7-dihydro-6H- (Methoxycarbonyl)prop ion dibenz[b ,dlazepin-6-one dihydro-6H-d ibenz[b,dllazepin-6- ic acid one (Aldrich) 7C-87 5-{N '-(4-phenylbutyryl)-L- 4-phenylbutyric acid 5-(L-alaninyl)-amino-7- C-P 456.2 (Aldrich) methyl- 7-d ihydro-6Hd ihydro-6H-dibenz[b ,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-88 5- (N'-(3-(benzylthio)-propionyl)-L- 3-(benzylthio)-propionic 5-(L-alaninyl)-amino-7- C-P 488.2 acid methyl-S ,7-dihydro-6Hd ihydro-6H-dibenz[b,djazepin-6- (Sigma-Aldrich Rare) dibenz~b,dlazepin-6-one _one I _I_ Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 7C-89 -methylpentanoyl)-L- 3-methylpentanoic acid 5-(L-alanin~l)-amino-7- C-P 408.2 (Aldrich) methyl-5 ,7-dihydro-6Hdihydro-6H-dibenz[b ,dlazepin-6- dibenz[b ,djazepin-6-one one 7C-90 5- -(7-carbomethoxyheptanoyl)- suberic acid monomethyl 5-(L-alaninyl)-amino-7- C-P 480.2 L-alaninyl} -amino-7-methyl-5 ester 7- methyl-S ,7-dihydro-6Hdihydro-6H-dibenz~b dazepin-6- carbomethoxyheptanoic dibenz[b,dlazepin-6-one one acid 7C-9 1 -(2-indanylacetyl)-L- 2-indanylacetic acid 5 -(L-alaninyl)-amino-7- C-P 468.2 alaninyl} -amino-7-methyl-5 (Lancaster) methyl-S ,7-dihydro-6Hd ihydro-6H-d ibenz[b ,dlazepin-6- dibenz[b ,djazepin-6-one one 7C'-92 N'-(5-Carbomethoxypentanoyl)- monomethyl adipate, 5- 5-(L-alaninyl)-amino-7- C-P 452.2 L-alaninyl }-amino-7-methyl-5 Carbomethoxypentanoic methyl- 7-dihydro-6Hdihydro-611-dibenzllb,dlazepin-6- acid dibenz[b,djazepin-6-one 7C-93 5-{N'-(2-methyl-3- 2-methyl-3- 5-(L-alaninyl)-amino-7- C-P 482.2 Benzofuranacetyl)-L-alaninyl}- Benzof'uranacetic acid methyl-S ,7-dihydro-6H- ,7-dihydro-6H- (Maybridge) d ibenz[b azepin-6-one dibenz[b,djazepin-6-one 7C-94 5-{N'-(propionyl)-L-alaninyl)- propionic acid 5-(L-alaninyl)-amino-7- C-P 366.1 ,7-dihydro-6H- (Aldrich) methyl-S ,7-dihydro-6Hdibenzlb,djazepin-6-one dibenzl~b,djazepin-6-one Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 7C-95 5J{ N' -(3-methoxypropionyl)-L- 3-methoxypropionic acid 5-(L-alanin~l)-amino-7- c-P 396. 1 (Aldrich) methyl- 7-dihydro-6Hdihydro-6H-d ibenz[b ,djazepin-6- dibenz[b ,d]azepin-6-one one 7C-96 5-(L-alaninyl)-amino-7- C-P 460.2 fluorophenyl)propionyl)-L- fluorophenyl)propionic methyl-S ,7-dihydro-6Halaninyl }-amino-7-methyl-5 acid dibenz[b ,djazepin-6-one dihydro-6H-dibenz[b ,dlazepin-6- (Trans World) one 7C-97 34(4- 5-(L-alaninyl)-amino-7- C-P 476.1 fluorophenoxy)propionyl)-L- fluorophenoxy)propionic methyl-5 ,7-dihydro-6Halaninyl) -amino-7-methyl-5 acid dibenz[b ,dlazepin-6-one d ihydro-6H-dibenz[b ,dlazepin-6- (Maybridge) one 7C-98 -(4-toluenesulfonylacetyl)-L- 4-toluenesulfonylacetic 5-(L-alaninyl)-amino-7- C-P 506.1 alaninyl}-amino-7-methyl-5,7- acid methyl-5,7-dihydro-6Hd ihydro-6H-d ibenb ,djazepin-6- (Lancaster) dibenzlb ,d~azepin-6-one one 7C-99 N' -(3-pentenoyl)-L-alaninyl)}- 3-pentenoic acid 5-(L-alaninyl)-amino-7- C-P 392.2 ,7-dihydro-6H- (Fluka) methyl- 7-dihydro-6Hdibenz[b,d]azepin-6-one I_ dibenz[b ,dlazepin-6-one Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 7C-100 5-{N 5-(L-alanin~l)-amino-7- c-P 540.1, dichlorophenoxy)butyryl)-L- dichlorophenoxy)butyric methyl-S ,7-dihydro-6H- 542.1 alaninyl) -amino-7-methyl-5 acid dibenz[b,dlazepin-6-one d ihydro-6H-d ibenz[b ,d]azepin-6- (Aldrich) one 7C- 101 5-{N 3-dichlorophenoxyacetyl)- 2, 3-dichlorophenoxyacetic 5-(L-alaninyl)-amino-7- C-P 512.1, acid methyl-S ,7-dihydro-6H- 514.1 dihydro-6H-dibenz[b,d]azepin-6- (Aldrich) dibenztb ,dlazepin-6-one one 7C-102 5-(L-alaninyl)-amino-7- C-P 504.1, chlorobenzoyl)propionyl)-L- chlorobenzoyl)propionic methyl-S ,7-dihydro-6H- 506.1 alaninyl}-amino-7-methyl-5,7- acid dibenz[b,dlazepin-6-one dihydro-6H-dibenz[b,djazepin-6- (Aldrich) one 7C- 103 '-fluorosuccinanilyl)-L- 4' -fluorosuccinanilic acid 5-(L-alaninyl)-amino-7- C-P 503.2 alaninyl} -amino-7-methyl-5 (Sigma-Aldrich Rare) methyl- 7-dihydro-6Hdihydro-6H-dibenz[b ,djazepin-6- dibenz[b,dlazepin-6-one one 7C-104 n- 5-(L-alaninyl)-amino-7- C-P 589.3 (diphenylmethyl)glutaramyl)-L- (diphenylmethyl)glutarami methyl- 7-dihydro-6Hc acid dibenzllb,d~azepin-6-one dihydro-6H-dibenz[b,djazepin-6- (Sigma-Aldrich Rare) __one I I Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 7C- 105 5- N'-(2-fluorophenylacetyl)-L- 2-fluorophenylacetic acid 5-(L-alaninyl)-amino-7- C-P 446.2 alaninyl) -amino-7-methyl-5 (Aldrich) methyl-S ,7-dihydro-6Hd ihydro-6H-d ibenz[b,d]azepin-6- dibenz[b ,d]azepin-6-one one 7C- 106 5-{N '-(cyanoacetyl)-L-alaninyl}- cyanoacetic acid 5-(L-alaninyl)-amino-7- C-P 377.1 amino-7-methyl-S ,7-dihydro-6H- (Aldrich) methyl- 7-dihydro-6Hdibenz[b ,d]azepin-6-one dibenz[b,dlazepin-6-one 7C-107 5-{N'-(succinanilyl)-L-alaninyl}- succinanilic acid 5-(L-alaninyl)-amino-7- C-P 485.2 amino-7-methy I-S,7-dihydro-6H- (Sigma-Aldrich Rare) methyl- 7-dihydro-6Hdibenzlb ,djazepin-6-one dibenz[b,d]azepin-6-one 7C-108 ,4-dichlorophenoxyaceyl)- 2 ,4-dichlorophenoxyacetic 5-(L-alaninyl)-amino-7- C-P 1512.1, acid methyl-S ,7-dihydro-6H- 514.1 dihydro-6H-dibenz[b ,d]azepin-6- (Aldrich) d ibenz[b ,d]azepin-6-one one 7C-109 S N'-(2-nitrophenylacetyl)-L- 2-nitrophenylacetic acid 5-(L-alaninyl)-amino-7- C-P 473.2 alaninyl}-amino-7-methyl-S (Aldrich) methyl-S ,7-dihydro-6dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,djazepin-6-one one 7C-1 10 -(beta-propylhydrocinnarnyl)- beta-propylhydrocinnamic 5-(L-alaninyl)-amino-7- C-P 484.3 L-alaninyl}-amino-7-methyl-S acid methyl-S ,7-dihydro-6Hdihydro-6H-dibenz[b,djazepin-6- (Sigma-Aldrich Rare) dibenz[b ,djazepin-6-one one__ Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 7C-1 I11 5-(L-alanin ])-amino-7- C-P 498.2 d imethylbenzoyl)propiony dimethylbenzoyl)propionic methyl-S ,7-dihydro-6Halaninyl} -amino-7-methyl-5 acid dibenz[b ,dlazepin-6-one d ihydro-6H-dibenz[b ,d~azepin-6- (Sigma-Aldrich Rare) one 7C-1 12 5-{N'-(2-fluoro-3- 2-fluoro-3- 5-(L-aianinyl)-amino-7- C-P 514.3 (trifluoromethyl)phenylacetyl)-L- (trifluoromethylI)pheny lace methyl-5 ,7-dihydro-6Halaninyl }-amino-7-methyl-5 tic acid dibenz~b ,djazepin-6-one d ihydro-6H-dibenzlb ,d]azepin-6- (Fluorochem) one 7C-113 ,4,6-trifluorophenylacetyl)- 2,4,6-trifluorophenylacetic 5-(L-alaninyl)-amino-7- C-P 482.2 acid methyl-S ,7-dihydro-6Hdihydro-6H-dibenz[b ,dlazepin-6- (Fluorochem) dibenz[b,dlazepin-6-one one 7C-1 14 5-{N'-(4-fluoro-2- 4-fluoro-2- 5-(L-alaninyl)-amino-7- C-P 514.2 (trifluoromethyl)phenylacetyl)-L- (trifluoromethylI)pheny lace methyl-S. 7-dhydro-6H4tic acid dibenz[b ,djazepin-6-one dihydro-6H-dibenz[b ,djazepin-6- (Fluorochem) one 7C-1 15 5-{N'-(2-fluoro-4- 2-fluoro-4- 5-(L-alaninyl)-amino-7- C-P 514.2 (trifluoromethyl)phenylacetyl)-L- (trifluoromethyl)phenylace methyl-5 ,7-dihydro-6Halaninyl }-amino-7-methyl-5 tic acid dibenz[b ,djazepin-6-one dihydro-6H-dibenz[b,djazepin-6- (Fluorochem) __one I I_ _I_ Example Compound Starting Material 1 Starting Material 2 General MVS No. Procedure 7C- 116 5-{N '-(4-hydroxyphenylacetyl)-L- 4-hydroxyphenylacetic 5-(L-alanin~l)-amino-7- C-P 444.2 alaninyl} -amino-7-methyl-5 acid methyl-S ,7-dihydro-6Hdihydro-6H-d ibenz[b ,dlazepin-6- (Aldrich) dibenz[b ,djazepin-6-one one 7C- 117 5- -(4-methoxyphenoxyacetyl)- 4-methoxyphenoxyacetic 5-(L-alaninyl)-amino-7- c-P 474.2 acid methyl-S. 7-d ihydro-6Hdihydro-6H-dibenz[b ,dlazepin-6- (Lancaster) d ibenz[b azepin-6-one one 7C-I 18 5-{N'-(2-methoxyphenylacetyl)-L- 2-methoxyphenylacetic 5-(L-alaninyl)-amino-7- C-P 458.2 acid methyl-5 ,7-dihydro-6H4dihydro-6H-dibenz[b,dlazepin-6- (Aldrich) dibenz[b,djazepin-6-one one 7C- 119 '-(2-bromophenylacetyl)-L- 2-bromophenylacetic acid 5-(L-alaninyl)-amino-7- C-P -508. 1 (Aldrich) methyl-S ,7-dihydro-6Hdihydro-6H-dibenz[b ,djazepin-6- dibenz[b ,dlazepin-6-one one 7C- 120 5- -(4-benzyloxyphenoxyacetyl)- 4-benzyloxyphenoxyacetic 5-(L-alaninyl)-amino-7- C-P 550.2 acid methyl-S ,7-dihydro-6Hdihydro-6H-dibenz[b ,dlazepin-6- (Lancaster) dibenzlb azepin-6-one one 7C- 121 5- -(4-hydroxyphenoxyacetyl)-L- 4-hydroxyphenoxyacetic 5 -(L-alaninyl)-amino-7- C-P 460.2 alaninyl} -amino-7-methyl-5 acid methyl-S ,7-dihydro-6Hdihydro-6H-dibenz[b ,djazepin-6- (Acros) dibenzllb,d]azepin-6-one _one I _1 Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 7C- 122 5N-(levulinyl)-L-alaninyl levulinic acid 5-(L-alanin ])-amino-7- C-P 408.2 anmino-7-methyl 7-dihydro-6Hi- (Aldrich) methyl- 7-dihydro-6Hdibenz[b,djazepin-6-one dibenzllb,dlazepin-6-one 7C- 123 5- {N '-(2-hydroxyphenylacetyl)-L- 2-hydroxyphenylacetic 5-(L-alaninyl)-amino-7- C-P 444.2 alaninyl} -amino-7-methyl-5 acid methyl-S. 7-d ihydro-6Hdihydro-6H-dibenz[b,djazepin-6- (Aldrich) dibenz[b,dJazepin-6-one one 7C-124 3,4-dimethoxyphenylacetic 5-(L-alaninyl)-amino-7- C-P 488.2 dimethoxypheny lacetyl)-L- acid methyl- 7-dihydro-6Halaninyl} -amino-7-methyl-5 (Aldrich) d ibenz[b ,d]azepin-6-one dihydro-6H-dibenz[b,djazepin-6one 7C-125 5-(L-alaninyl)-amino-7- C-P 500.2 methoxybenzoyl)propionyl)-L- methoxybenzoyl)propionic methyl-S ,7-dihydro-6Hacid dibenz[b,d]azepin-6-one dihydro-6H1-d ibenz[b ,d]azepin-6- (Aldrich) one 7C-126 fenbufen 5-(L-alaninyl)-amino-7- C-P 546.2 Phenylbenzoyl)propionyl)-L- Phenyl benzoylI)prop ionic methyl-S ,7-dihydro-6Halaninyl)-amino-7-methyl-5,7- acid dibenzllb,d]azepin-6-one dihydro-6H-dibenz[b ,d]azepin-6- (Sigma-Aldrich Rare)
IIL
Example Compound Starting Material 1 Starting Material 2 General MS No. 7C- 127 N' -hydroxyphenylacetyl)-L- 3-hydroxyphenylacetic 5 -(L-alaninyt)-amino-7- C-P 444.2 alaninyl} -amino-7-methyl-5 acid methyl-S ,7-dihydro-6Hdihydro-6H-dibenzlb,dlazepin-6- (Aldrich) dibenz[b ,d]azepin-6-one one 7C- 128 -(N-acetyl-N-phenylglycinyl)- N-acetyl-N-phenylglycine 5-(L-alaninyl)-amino-7- C-P 485.2 (Kodak) methyl-S ,7-dihydro-6Hdihydro-6H-dibenz[b,d]azepin-6- dibenz[b,djazepin-6-one one 7C-129 -(thiophene-3-acetyl)-L- thiophene-3 -acetic acid. 5-(L-alaiiinyl)-amino-7- C-P 434.1 alaninyl} -amino-7-methyl-5 (Acros) methyl-S ,7-dihydro-6Hdihydro-6H-dibenz[b ,d]azepin-6- dibenzlb ,dlazepin-6-one one 7C- 130 5-{N -(6-phenylhexanoyl)-L- 6-phenylhexanoic acid 5-(L-alaninyl)-amino-7- C-P 484.3 (Avocado) methyl- 7-dihydro-6Hdihydro-6H-dibenzb,djazepin-6- dibenz[b dazepin-6-one 7C- 131 -(cyclohexanebutyryl)-L- cyclohexanebutyric acid 5-(L-alaninyl)-amino-7- C-P 1462.3 alaninyl }-amino-7-methyl-5 (Aldrich) methyl- 7-dihydro-6Hd ihydro-6H-d ibenz[b ,djazepin-6- dibenz[b,dlazepin-6-one one 7C- 132 5-{N ,5-trifluorophenylacetyl)- 2,3 ,5-trifluorophenylacetic 5-(L-alaninyl)-amino-7- C-P 482.2 acid methyl-S ,7-dihydro-6Hdihydro-6H-dibenz[b,d]azepi n-6- (Fluorochem) dibenz[b,djazepin-6-one Example Compound Starting Material I Starting Material 2 General MS No. ________Procedure 7C- 133 5-{N ,4,5-trifluorophenylacetyl)- 2 ,4,5-trifluorophenylacetic 5-(L-alanin~l)-amino-7- C-P 482.2 L-alaninyl} -amino-7-methyl-5 acid methyl-S ,7-dihydro-6Hdihiydro-6H-dibenz[b,djazepin-6- (Fluorochern) dibenz[b ,dlazepin-6-one one 7C- 134 -(vinylacetyl)-L-alaninyl}- vinylacetic acid 5-(L-alaninyl)-amino-7- C-P 378.2 ,7-dihydro-6H- (Aldrich) methyl-S ,7-dihydro-6Hdibenz[b ,dlazepin-6-one dibenz~b ,djazepin-6-one 7C- 135 5- '-(3-methylthiopropionyl)-L- 3-methyithioprop ionic acid 5-(L-alaninyl)-amino-7- C-P 412.1 alaninyl }-amino-7-methyl-5 (Lancaster) methyl-S ,7-dihydro-6Hdihydro-6H-dibenz[b,djazepin-6- dibenz[b ,d]azepin-6-one one__ 7C-136 5-{N'-(3-nitrophenylacetyl)-L- 3-nitrophenylacetic acid 5-(L-alaninyl)-amino-7- C-P 473.2 (Aldrich) methyl-S ,7-dihydro-6Hdihydro-6fl-dibenz[b,dlazepin-6- dibenz[b ,dlazepin-6-one one 7C- 137 -(n-tert-butylsuccinamyl)-L- n-tert-butylsuccinamic acid 5-(L-alaninyl)-amino-7- C-P 465.2 (Sigma-Aldrich Rare) methyl- 7-dihydro-6Hdihydro-6H-dibenzlb azepin-6- dibenz[b,dlazepin-6-one one XC-138 5-{N -(4-bromophenylacetyl)-L- 4-bromophenylacetic acid 5-(L-alaninyl)-amino-7- C-P 506.1, (Aldrich) methyl-S ,7-dihydro-6H- 508.1 dihydro-6H-dibenzllb,d]azepin-6- dibenz[b ,djazepin-6-one one__ Example Compound Starting Material 1 Starting Material 2 General MS No. 7C-139 5-(L-alanin~l)-amino-7- C-P 488.2 fluorobenzoyl)propionyl)-L- fluorobenzoyl)propionic methyl-S ,7-dihydro-6Halaninyl) -amino-7-methyl-5 acid dibenz[b ,d]azepin-6-one dihydro-6H-dibenz[b ,dlazepin-6- (Aldrich) one 7C- 140 5- -(o-chlorophenoxyacetyl)-L- o-chiorophenoxyacetic 5-(L-alaninyl)-amino-7- C-P 478.1, alaninyl} -amino-7-methyl-5 acid methyl- 7-dihydro-6H- 480.1 dihydro-6H-dibenz[b,dlazepin-6- (Lancaster) dibenzllb,d]azepin-6-one one 7C- 141 5- -(p-tolylaceyl)-L-alaninyl} p-tolylacetic acid 5-(L-alaninyl)-amino-7- C-P 442.2 7-dihydro-6H- (Aldrich) methyl- 7-dihydro-6Hdibenz[b,d]azepin-6-one dibenz[b ,d]azepin-6-one 7C- 142 5- -(m-tolylacetyl)-L-alaninyl} m-tolylacetic acid 5-(L-alaninyl)-amino-7- C-P 442.2 ,7-dihydro-6H- (Aldrich) methyl-S ,7-dihydro-6Hdibenz[b ,d]azepin-6-one dibenz[b,djazepin-6-one 7C- 143 ,4-dichlorophenylacetyl)- 3 ,4-diclilorophenylacetic 5-(L-alaninyl)-amino-7- C-P 496.1, acid methyl-S ,7-dihydro-6H- 498.1 dihydro-6H-dibenz[b ,dlazepin-6- (Fairfield) dibenz[b ,djazepin-6-one one 7C- 144 5-f{ N'-(4-chlorophenoxyacetyl)-L- 4-chiorophenoxyacetic 5-(L-alaninyl)-amino-7- C-P 478.1, acid methyl-S ,7-dihydro-6H- 480.2 dihydro-6H-dibenz[b,djazepin-6- (Grand Island Biological) dibenz[b ,djazepin-6-one _one I1- Example Compound Starting Material I Starting Material 2 General MS No. Procedure 7C- 145 5- -(3-methylphenoxyacetyl)-L- 3-methyiphenoxyacetic 5-(L-alanin~l)-amino-7- C-P 458.2 alaninyl }-amino-7-methyl-5 acid methyl-S ,7-dihydro-6Hd ihydro-6H-dibenz[b ,djazepin-6- (Lancaster) dibenz[b ,dlazepin-6-.one one 7C- 146 5- -(4-isopropylphenoxyacetyl)- 4-isopropyiphenoxyacetic 5-(L-alaninyl)-amino-7- C-P 486.2 acid methyl-S ,7-dihydro-6Hdihydro-6H-dibenzllb,dlazepin-6- (Lancaster) dibenzllb,dlazepin-6-one one 7C- 147 -(4-phenoxyphenylacetyl)-L- 4-phenoxypheny lacetic 5-(L-alaninyl)-amino-7- C-P 520.2 alaninyl} -amino-7-methyl-5 acid methyl-S ,7-dihydro-6Hd ihydro-6H-d ibenz[b,djazepin-6- (Trans World) dibenz[b azepin-6-one one 7C- 148 5 -(phenylmercaptoacetyl)-L- phenylmercaptoacetic acid 5-(L-alaninyl)-amino-7- C-P 460.2 (Aldrich) methyl-S ,7-dihydro-6Hdihydro-6H-dibenz jb ,d]azepin-6- dibenz[b ,dlazepin-6-one one 7C- 149 5- -(4-ethoxyphenylacetyl)-L- 4-ethoxyphenylacetic acid 5-(L-alaninyl)-amino-7- C-P 472.2 alaninyl }-amino-7-methyl-5 (Aldrich) methyl-S. 7-dihydro-6Hdihydro-6H-dibenz[b,djazepin-6- dibenz[b ,d]azepin-6-one one Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 7C- 150 2 ,5-dimethoxyphenylacetic 5-(L-alanin~l)-amino-7- C-P 488.2 dimethoxyphenylacetyl)-L- acid methyl-S ,7-dihydro-6Halaninyl )-amino-7-methyl-5 (Aldrich) dibenz[b dihydro-6H-dibenz[b,d]azepin-6one 7C- 151 5-f{N' -(o-tolylacetyl)-L-alaninyl)- o-tolylacetic acid 5-(L-alaninyl)-amino-7- C-P 442.2 ,7-dihydro-6H- (Aldrich) methyl-5 ,7-dihydro-6Hdibenz[b dazepin-6-one dibenz[b ,djazepin-6-one 7C- 152 3-diphenylpropionyl)-L- 3, 3-diphenylpropionic acid 5-(L-alaninyl)-amino-7- C-P 518.2 alaninyl} -amino-7-methyl-5 (Aldrich) methyl-S ,7-dihydro-6Hdihydro-6H-dibenz[b azepin-6- d ibenz[b ,dlazepin-6-one one 7C- 153 5- '-(3-phenoxypropionyl)-L- 3 -phenoxyprop ionic acid 5-(L-alaninyl)-amino-7- C-P 458.2 (Aldrich) methyl-S ,7-dihydro-6Hdihydro-6H-dibenz[b ,dlazepin-6- dibenz[b ,dlazepin-6-one one 7C- 154 4- 5-(L-alaninyl)-aniino-7- C-P 496.2 (trifluoromethyl)phenylacetyl)-L- (trifluoromethyl)pheny lace methyl-S ,7-dihydro-611alaninyl} -amino-7-methyl-5 tic acid dibenz[b ,dlazepin-6-one dihydro-6H-dibenz[b,d]azepin-6- (Maybridge) Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 7C- 155 5-{N '-((4-inethylphenoxy)acetyl)- (4-methylphenoxy)acetic 5-(L-alanin~l)-amino-7- C-P 458.2 L-alaninyl}-amino-7-methyl-5,7- acid methyl-5,7-dihydro-6Hdihydro-6H-dibenz[b,djazepin-6- (Aldrich) dibenzjb ,djazepin-6-.one one 7C- 156 5-{N '-(2-phienoxyphenylacetyl)-L- 2-phenoxyphenylacetic 5-(L-alaninyl)-amino-7- C-P 520.2 alaninyl }-amino-7-methyl-5 acid mty5,7-d ihydro-6Hdihydro-6H-dibenzllb,d]azepin-6- (Trans World) dibenz[b,dljazepin-6-one 7C- 157 5- -phenoxyphenylacetyl)-L- 3-phenoxyphenylacetic 5-(L-alaninyl)-amino-7- C-P 520.2 alaninyl} -amino-7-methyl-5 acid mty5,7-dihydro-6Hdihydro-6H-dibenzlb ,d]azepin-6- (Aldrich) d ibenz[b ,dlazepin-6-one one 7C- 158 5-{N ,4-dichlorophenoxyacetyl)- 3 ,4-dichlorophenoxyacetic 5-(L-alaninyl)-amino-7- C-P 512. 1, acid methyl-S ,7-dihydro-6H- 514.1 dihydro-6H-dibenz[b,djazepin-6- (Aldrich) dibenz[b,d]azepin-6-one one 7C- 159 5-{N '-(4-fluorophenoxyacetyl)-L- 4-fluorophenoxyacetic acid 5-(L-alaiiinyl)-amino-7- C-P 462.2 (Aldrich) methyl-S ,7-dihydro-6Hd ihydro-6H-djbenz[b,d]azepin-6- dibenz[b,d~azepin-6-one one Example Compound Starting Material 1 Starting Material 2 General MIS No. 7C-160- 3,4,5- 5-(L-alanin~l)-amino-7- C-P 518.2 trimethoxyphenylacetyl)-L- trimethoxyphenylacetic rnethyl-5 ,7-dihydro-6Halaninyl) -amino-7-methyl-5 acid dibenzlb ,dlazepin-6-one dihydro-6H-dibenz[b,djazepin-6- (Aldrich) one 7C- 161 ichlorophenylacetyl)- 2 ,4-dichlorophenylacetic 5-(L-alaninyl)-amino-7- C-P 496.1, L-alaninyl} -amino-7-methyl-5 acid methyl-S ,7-dihydro-6H- 498.1 dihydro-6H-dibenz[b,djazepin-6- (Fairfield) dibenz[b,d]azepin-6-one one 7C-162 5-{N'-(4-thianaphthenacetyl)-L- 4-thianaphthenacetic acid 5-(L-alaninyl)-amino-7- C-P 484.2 alaninyl} -amino-7-methyl-5 (Aldrich) methyl-S ,7-d ihydro-6Hd ihydro-6H-d ibenz[b ,djazepin-6- dibenz[b ,djazepin-6-one one 7C- 163 N' -(methoxyacetyl)-L-alaninyl} methoxyacetic acid 5-(L-alaninyl)-amino-7- C-P 382.2 ,7-dihydro-6H- (Aldrich) methyl-S ,7-dihydro-6Hdibenzllb,dlazepin-6-one dibenzllb,dlazepin-6-one XC-164 5-{N'-(ethoxyacetyl)-L-alaninyl}- ethoxyacetic acid 5-(L-alaninyl)-amino-7- C-P 396.2 ,7-dihydro-6H- (Aldrich) methyl-S ,7-d ihydro-6Hdibenz[b ,dlazepin-6-one dibenz[b ,djazepin-6-one 7C- 165 5-{N '-(phenoxyacety l)-L-alaninyl)}- phenoxyacetic acid 5-(L-alaninyl)-amino-7- C-P 444.2 ,7-dihydro-6H- (Aldrich) methyl-S ,7-dihydro-6Hdibenz~b ,dlazepin-6-one dibenzllb,dlazepin-6-one Example Compound Starting Material 1 Starting Material 2 General MIS No. Procedure 7C- 166 N' -(3-methoxyphenoxyacetyl)- 3-methoxyphenoxyacetic 5-(L-alanin~l)-amino-7- C-P 474.2 acid methyl- 7-dihydro-6Hdihydro-6f -dibenz[b,djazepin-6- (Aldrich) one 7C-167 5-{N'-(4-butoxyphenylacetyl)-L- 4-butoxyphenylacetic acid 5-(L-alaninyl)-amino-7- C-P 500.3 alaninyl} -amino-7-methyl-5 (Lancaster) methyl-5 ,7-dihydro-6Hdihydro-6H-dibenz[b,dlazepin-6- dibenz[b,dlazepin-6-one one 7C-168 5-(L-alaninyl)-amino-7- C-P 472.2 methoxyphenyl)propionyl)-L- methoxyphenyl)propionic methyl-5 ,7-dihydro-6Halaninyl }-amino-7-methyl-5 acid dibenz[b ,d]azepin-6-one d ihydro-6H-d ibenz[b ,djazepin-6- (Aldrich) one 7C- 169 5-{N N-dimethylsuccinamyl)- N, N-dimethylsuccinamic 5-(L-alaninyl)-amino-7- C-P 437.2 L-alaninyl} -amino-7-methyl-5 acid methyl- 7-dihydro-6Hd ihydro-6H-d ibenz[b ,d]azepin-6- (Lancaster) dibenz[b ,dlazepin-6-one one 7C-170 5-(L-alaninyl)-amino-7- C-P 486.2 methylenedioxyphenyl)propiony methylenedioxyphenyl)pro, methyl-S ,7-dihydro-6H- L-alaninyl}-amino-7-methyl-5,7- pionic acid dibenz[b,d]azepin-6-one dihydro-6H-dibenz[b ,d]azepin-6- (Lilly) Example Compound Starting Material I Starting Material 2 General MS No. Procedure 7C- 171 5-{N'-(2-Chloro-6- 2-Chloro-6- 5-(L-alaninl)-amino-7- C-P 480.1, fluorophenylacetyl)-L-alaninyl)}- fluoropheny lacetic acid methyl-S ,7-dihydro-6H- 482.1 ,7-dihydro-6H- dibenz[b ,djazepin-6-.one dibenz[b,d]azepin-6-one 7C- 172 5-{N '-(2,5-difluorophenylacetyl)-L- 2,5-difluorophenylacetic 5-(L-alaninyl)-amino-7- C-P 464.2 acid methyl-S ,7-dihydro-6Hdihydro-6H-dibenzlb ,d]azepin-6- (Aldrich) d ibenzlb,dlazepin-6-one one 7C- 173 5- -(pentafluorophenoxyacetyl)- pentafluorophenoxyacetic 5-(L-alaninyl)-amino-7- C-P 534.2 acid methyl-S ,7-dihydro-6Hdihydro-6H-dibenz[b ,d]azepin-6- (Aldrich) dibenz[b,dllazepin-6-one one__ 7C- 174 5-{N 3,5- 5-(L-alaninyl)-amino-7- C-P 564.2 bis(trifluoromethyl)phenylacetyl)- bis(trifluoromethyl)phenyl methyl-S ,7-dihydro-6Hacetic acid dibenz[b ,djazepin-6-one dihydro-6H-dibenzllb,d]azepin-6- (Aldrich) one 7C-1 75 3 ,5-dimethylphenoxyacetic 5-(L-alaninyl)-amino-7- C-P 472.2 dimethylphenoxyacetyl)-L- acid methyl-S ,7-dihydro-6Halaninyl} -amino-7-methyl-5 (Sigma-Aldrich Rare) dibenz[b azepin-6-one dihydro-6H-dibenz[b,djazepin-6- I_ one Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 7C- 176 5-(N'-(4-chlorophenylacetyl)-L- 4-chlorophenylacetic acid 5-(L-alanin~l)-amino-7- C-P 462.1, alaninyl} -amino-7-methyl-5 (Aldrich) methyl- 7-dihydro-6H- 464.1 d ihydro-6H-dibenz[b ,dlazepin-6- dibenz[b,d]azepin-6-.one one 7C- 177 5- N'-(3-chlorophenoxyacetyl)-L- 3-chiorophenoxyacetic 5-(L-alaninyl)-amino-7- C-P 478.1, acid methyl-S ,7-dihydro-6H- 480.2 dihydro-6H-dibenz[b,dlazepin-6- (Lancaster) dibenz[b ,dlazepin-6-one one 7C-178 5-{N'-(benzo thiophene-3- benzo thiophene-3- 5-(L-alaninyl)-amino-7- c-P 484.2 acetyl)-L-alaninyl} -amino-7- acetic acid methyl-S ,7-dihydro-6Hmethyl- 7-dihydro-6H- (Lancaster) d ibenz[b ,dlazepin-6-one dibenz[b,d]azepin-6-one______ 7C-179 5-{N 3 ,5-dimethoxyphenylacetic 5-(L-alaninyl)-amino-7- C-P 488.2 dimethoxyphenylacetyl)-L- acid methyl-S ,7-dihydro-6H- (Aldrich) dibenz[b,djazepin-6-one d ihydro-6H-dibenz[b ,djazepin-6one 7C- 180 5-{N '-(2,5-dimethylphenylacetyl)- 2,5-dimethylphenylacetic 5-(L-alaninyl)-amino-7- C-P 456.2 acid methyl-S ,7-dihydro-6Hd ihydro-6H-d ibenz[b,d]azepin-6- (Lancaster) dibenz[b ,dlazepin-6-one one XC-181 N' -(mesity lacetyl)-L-alaninyl}- mesitylacetic acid 5-(L-alaninyl)-amino-7- C-P 470.2 am ino-7-methyl-5 ,7-d ihydro-6H- (Lancaster) methyl-S ,7-dihydro-6Hdibenz[b ,diazepin-6-one dibenzllb,djazepin-6-one Example Compound Starting Material 1 Starting Material 2 General MVS No. Procedure 7C- 182 '-(4-biphenylacetyl)-L- 4-biphenylacetic acid 5-(L-alanin~l)-amino-7- C-P 504.2 (Lancaster) methyl-S ,7-dihydro-6Hdihydro-6H-d ibenz[b,dlazepin-6- dibenzlb ,dlazepin-6-one one 7C- 183 5-{N'-(N-(tert-butoxycarbonyl)-3- boc-beta-ala-oh N-(tert- 5-(L-alaninyl)-amino-7- C-P 381.2, aminopropionyl)-L-alaninyl butoxycarbonyl)-3- methyl-S ,7-dihydro-6H- 481.2 ,7-dihydro-6H- aminopropionic acid dibenz[b ,dlazepin-6-one dibenzjlb,d]azepin-6-one (Sigma) 7C- 184 -(trans-styrylacetyl)-L- trans-styrylacetic acid 5-(L-alaninyl)-amino-7- C-P 454.2 alaninyl} -amino-7-methyl-5 (Aldrich) methyl-S ,7-dihydro-6Hdihydro-6H-dibenz[b,djazepin-6- dibenzlb, dlazepin-6-one one 7C- 185 5- {N -(4-acetamidobutyryl)-L- 4-acetamidobutyric acid 5-(L-alaninyl)-amino-7- C-P 437.2 alaninyl }-amino-7-methyl-5 (Aldrich) methyl-S ,7-dihydro-6Hd ihydro-6H-dibenz[b ,d]azepin-6- dibenz~b ,dlazepin-6-one one 7C- 186 5-(L-alaninyl)-amino-7- C-P 476.2, chlorophenyl)propionyl)-L- chlorophenyl)propionic methyl-S ,7-dihydro-6H- 478.2 acid d ibenz[b ,d]azepi n-6-one d ihydro-6H-d ibenz[b ,d~azepiin-6- (Trans World) one 7C-187 5-{N'-(butyryl)-L-alaninyl}-amino- butyric acid 5-(L-alaninyl)-amino-7- C-P 380.2 7-methyl-S ,7-dihydro-6H- (Aldrich) methyl-S ,7-dihydro-6Hdibenz jb ,djazepin-6-one dibenzlb ,djazepin-6-one Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 7C- 188 5-{N'-(trans-3-hexenoyl)-L- trans-3-hexenoic acid 5-(L-alaninl)-amino-7- C-P 406.2 (Aldrich) methyl-5 ,7-dihydro-6Hdihydro-6H-dibenz[b ,dlazepin-6- dibenz[b,dlazepin-6-one 7C-189 5-{N'-(5-phenylvaleryl)-L- 5-phenylv aleric acid 5-(L-alaninyl)-amino-7- c-P 470.2 alaninyl }-amino-7-methyl-5 (Aldrich) methyl-S ,7-dihydro-6Hdihydro-6H-dibenz[b ,dlazepin-6- dibenz[b ,dlazepin-6-one 7C- 190 5-(N 5-(L-alaninyl)-amino-7- C-P 472.2 methoxyphenyl)propionyl)-L- methoxyphenyl)propionic methyl- 7-dihydro-6Hacid dibenz[b ,d]azepin-6-one dihydro-6H-d ibeniz[b ,dllazepin-6- (Lancaster) one 7C- 191 5-{'-(4-chloro-beta- 4-chioro-beta- 5-(L-alaniny I)-amino-7- C-P 490.2, methylhydrocinnamyl)-L-alaninyl)}- methyihydrocinnamic acid methiyl-S. 7-dihydro-6H- 492.2 ,7-dihydro-6H- (Sigma-Aldrich Rare) d ibenz[b,dlazepin-6-one dibenz[b,djazepin-6-one_________ 7C-192 5-{N'-(3-(trifluoromethyl)butyryl)- 3-(trifluoromethyl)butyric 5-(L-alaninyl)-amino-7- C-P 448.2 L-alaninyl)-amino-7-methyl-s acid methyl- 7-dihydro-6Hdihydro-6H-dibenz[b,djazepin-6- (Fluorochem) dibenz[b dazepin-6-one one Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 7C- 193 N' -(methanesulfonylacetyl)-L- methanesulfonylacetic acid 5-(L-alanin~1)-amino-7- C-P 430.1 (Lancaster) methyl-S ,7-d ihydro-6Hdihydro-6H-d ibenz[b,dlazepin-6- dibenz[b ,dlazepin-6-one one 7C- 194 -(alpha-naphthoxyacetyl)-L,- alpha-naphthoxyacetic acid 5-(L-alaninyl)-amino-7- C-P 494.2 alaninyl} -amino-7-methyl-5 (Aldrich) methyl-5 ,7-dihydro-6Hdihydro-611-dibenz[b ,djazepin-6- dibenz[b ,dlazepin-6-one one 7C-195 5-(L-alaninyl)-amino-7- C-P 562.2 phenoxybenzoyl)propionyl)-L- phenoxybenzoyl)propionic methyl-S ,7-dihydro-6Halaninyl) -amino-7-methyl-5 acid dibenz[b ,dlazepin-6-one dihydro-6H-d ibenz[b ,djazepin-6- (Sigma-Aldrich Rare) one 7C-196 5-(L-alaninyl)-amino-7- C-P 538.2 trifluoromethylbenzoyl)propionyl)- trifluoromethylbenzoyl)pro methyl-S ,7-dihydro-6H- L-alaninyl }-amino-7-methyl-5 pionic acid d ibenz[b,djazepin-6-one dihydro-6H-dibenz[b,djazepin-6- (Sigma-Aldrich Rare) one 7C- 197 5-f{N'-(3-benzoylamino-3-phenyl- 3-benzoylamino-3-phenyl- 5-(L-alaninyl)-amino-7- C-P 561.2 propionyl)-L-alaninyl)}-amino-7- propionic acid methyl-S ,7-dihydro-6Hmethyl-S ,7-dihydro-6H- (Sigma-Aldrich Rare) dibenz[b,d]azepin-6-one dibenz[b Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 7C-198 4- levulinic acid oxime 4- 5-(L-alaninl')-amino-7- C-P 423.2 (hydroxyimino)pentanoyl)-L- (hydroxyimino)pentanoic methyl-S ,7-dihydro-6Hacid dibenz[b ,d]azepin-6-.one d ihydro-6H-d ibenz[b ,dlazepin-6- (Sigma-Aldrich Rare) one 7C- 199 5-{N -methylglutaranilyl)-L- 4 '-methylglutaranilic acid 5-(L-alaninyl)-amino-7- C-P 499.2 (Sigma-Aldrich Rare) methyl-S ,7-dihydro-6Hdihydro-6H-dibenz[b,dlazepin-6- dibenz[b,d]azepin-6-one one 7C-200 N' -((4-(4-ethyl-phenoxy)- (4-(4-ethyl-phenoxy)- 5-(L-alaninyl)-amino-7- C-P 564.2 phenoxy)-acetyl)-L-alaninyl phenoxy)-acetic acid methyl-S ,7-dihydro-6H- ,7-dihydro-6H- (Sigma-Aldrich Rare) dibenz[b ,d]azepin-6-one i dibenzlb ,d]azepin-6-one 7C-20 1 -(3-IBenzoyl-3- 3-Benzoyl-3- 5-(L-alaninyl)-amino-7- C-P 528.2, pheny Ipropionyl)-L-alaninyl}- phenylpropionic acid methyl-S ,7-dihydro-6H- 546.2 ,7-dihydro-6H- (Sigma-Aldrich Rare) dibenb ,d]azepin-6-one dibenz[b ,djazepin-6-one 7C-202 4- 5-(L-alaninyl)-amino-7- C-P 456.2, (liydroxymethyl)phenoxyacetyl)-L- (hydroxymethyl)phenoxy- methyl-S ,7-dihydro-6H- 474.2 alaninyl) -amino-7-methyl- 7- acetic acid dibenzlb ,dlazepin-6-one dihydro-6H-dibenz[b azepin-6- (Sigma) one__ Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 7C-203 5-{N'-(4,4,4-trifluorobutyryl)-L- 4,4,4-trifluorobutyric acid 5-(L-alanin~l)-amino-7- C-P 434.1 (Fluorochem) methiyl- 7-dihydro-6Hdihydro-6H-dibenzlb ,djazepin-6- dibenz[b ,djazepin-6-one one 7C-204 5-{N'-(3-isobutyrylamino-3-phenyl- 3-isobutyrylamino-3- 5-(L-alaninyl)-amino-7- C-P 527.3 propionyl)-L-alaninyl)}-amino-7- phenyl-propionic acid methyl-S ,7-dihydro-6Hmethyl-S ,7-dihydro-6H- (Sigma-Aldrich Rare) dibenz[b ,d]azepin-6-one dibenz[b 7C-205 5- {N '-((2-methylphenoxy)acetyl)- (2-methylphenoxy)acetic 5-(L-alaninyl)-amino-7- C-P 458.2 acid methyl-S ,7-dihydro-6Hdihydro-6H-dibenz[b,d]azepin-6- (Lancaster) d ibenz[b ,djazepin-6-one one 7C-206 3- 5-(L-alaninyl)-amino-7- C-P 506.2 (phenylsulfonyl)propionyl)-L- (phenylsulfonyl)propiomc methyl-S ,7-dihydro-6Hacid dibenz~b ,djazepin-6-one d ihydro-6H-dibenz[b ,dlazepin-6- (Aldrich) one XC-207 5-{N'-(4-nitrophenylacetyl)-L- 4-nitrophenylacetic acid 5-(L-alaninyl)-amino-7- C-P 473.2 alaninyl} -amino-7-methyl-5 (Aldrich) methyl-S ,7-dihydro-6Hdihydro-6H-dibenz[b ,dlazepin-6- dibenz[b,d]azepin-6-one one__ Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 7C-208 -ethoxypropionyl)-L- 3-ethoxypropionic acid 5-(L-alanin~l)-amino-7- C-P 410.2 alaninyl) -amino-7-methyl-5 (TCI) methyl-S ,7-dihydro-6Hdihydro-6H-d ibenz~b ,dlazepin-6- dibenz[b,d]azepin-6-one one 7C-209 ,3-difluoromandelyl)-L- 2,3-difluoromandelic acid 5-(L-alaninyl)-amino-7- C-P 480.2 alaninyl }-amino-7-methyl-5 (Fluorochem) methyl-5 ,7-dihydro-6Hdihydro-6H-dibenz[b ,d]azepin-6- dibenz[b,dlazepin-6-one one 7C-2 10 ,6-difluoromandelyl)-L- 2 ,6-difluoromandelic acid 5-(L-alaninyl)-amino-7- C-P 480.2 (Fluorochem) methyl-5 ,7-dihydro-6Hdihydro-6H-dibenz[b ,dlazepin-6- dibenz[b ,d]azepin-6-one one 7C-21 1 5-{N'-(4-fluoromandelyl)-L- 4-fluoromandelic acid 5-(L-alaninyl)-amino-7- C-P 462.2 alaninyl) -amino-7-methyl-5 (Lancaster) methyl-S ,7-dihydro-6Hdihydro-6H-dibenz[b,d]azepin-6- dibenz[b azepin-6-one one 7 C-2 12 5- ,5-difluoromandelyl)-L- 2, 5-difluoromandelic acid 5-(L-alaninyl)-amino-7- C-P 480.2 alaninyl) -amino-7-methyl-5 (Fluorochem) methyl-S ,7-dihydro-6Hdihydro-6H-dibenz[b ,dlazepin-6- dibenz[b ,d]azepin-6-one one 7C-2 13 5- {N-(dl-beta-phenyllactyl)-L- di-beta-phenyllactic acid 5-(L-alaninyl)-amino-7- C-P 458.2 (Sigma) methyl-S ,7-dihydro-6Hd ihydro-6H-dibenz[b ,dlazepin-6- dibenzllb,dJazepin-6-one _one I _I_ S *t S. a a S a a a 1
N
A~ ample Compound Starting Material 1 Starting Material 2 General MIS 0 N. Procedure 7C-214 5-{N'-(dl-mandelyl-L-alaninyl}- di-mandelic acid or dl- 5-(L-alanin~l)-amino-7- C-P 444.2 amino-7-methyl-5,7-dihydro-6H- a Ipha-hydroxyphenylacetic methyl-S 1 7-d ihydro-6Hacid dibenz~b,djazepin-6-one dibenzb,d]azepin-6-one (Aldrich) 7C-215 5-{N'-(p-chloromandelyl)-L- p-chloromandelic acid 5-(L-alaninyl)-amino-7- c-P 444.2, (Acros) methyl- 5,7-dihydro-6H- 478.1 dihydro-6H-dibenz[b,djazepin-6- d ibenztb,djazepin-6-one one 7C-2 16 5- N'-(1-alpha-hydroxy isocaproyl)- 1-alpha-hydroxy isocaproic 5-(L-alaninyl)-amino-7- C-P 424.2 L-alaniinyl} -amino-7-methyl-5 acid mty5,7-dihydro-611d ihydro-6H-d ibenzib,dJazepin-6- (Aldrich) dibenzllb,djazepin-6-one 7C-2 17 N' -(4-bromomandely 4-bromomandel ic acid 5-(L-alaninyl)-amino-7- C-P 522. 1, alaninyl) -amino-7-methyl-5 17- (Aldrich) methyl-S ,7-dihydro-6f1- 524. 1 d ihydro-6H-dibenz[b,djazepin-6- dibenz[b,dlazepin-6-one IC-218 5-j N-(-(+)-lactyl)-L-alaninyljamino-7-methyl-5,7-dihydro-6Hdibenz[b,djazepin-6-one l-(±)-lactic acid (Sigma) 5-(L-alaninyl)-amino-7methiyl-S ,7-dihydro-6Hdibenz[b,dlazepin-6.one C-P 382.2, 454.2 7C-2 19
I
-(d-3-phenylacetyl)-Lalaninyl)-amino-7-methyl1-5 7dihydro-6H-dibenz[b,dlazepin-6one -i 4--
I
d-3-phenylacetic acid (Aldrich) 5-(L-alaninyl)-amino-7methyl-S ,7-dihydro-6Hdibenzlb,dlazepin-6-one C-P 458.2 Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 7C-220 5-{N'-(5-methylhexanoyl)-L- 5-methyihexanoic acid 5-(L-alaninl)-amino-7- C-P 422.2 alaninyl }-amino-7-methyl-5 methyl-S ,7-dihydro-6Hdihydro-6H-dibenz[b,dlazepin-6- dibenz[b ,djazepin-6-.one oneII WO 98/28268 PCT/US97/22986 599 GENERAL PROCEDURE C-S Step A: Each amino acid (150 umol) was weighed into an 8-mL capacity vial and dissolved in 1.5 mL of 10% DMF in dichloromethane (DCM). To each vial was added 0.8 mL (175 umol) of a solution of 5-amino-7-methyl-5,7dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (481 mg, 1.75 mmol) (from Example 7-A) and 670 mg (1.75 mmol) of PP-HOBT (from Example C-AF) dissolved in 7.5 mL DMF. This was followed by the addition to each vial of 2 mL (approximately 200 umol) of a solution of EDC hydrochloride in DCM (383 mg, 2.0 mmol in 20 mL DCM). After rocking the vials at room temperature for 14 hours, approximately 100-125 mg of polystyrene-piperidine resin (approximately 3.6 mmol/g, 350 umol, 2.33 eq.) was added to each vial and rocking continued for 15 minutes. Methanol (2.5 mL) was added to each vial and the material put on a 1 g SCX column (Varian) pre-equilibrated with mL of MeOH and 5 mL of 10% MeOH/chloroform. After pushing the liquid through the column with nitrogen, the column was washed with 5 mL of MeOH/chloroform. The combined eluants (collected in 25 mL roundbottom flasks) were evaporated at reduced pressure with a warm water bath at 30-35 C and then further evaported in a vacuum oven at 40-45 C. When the net weight of the residues was below 100 mg, 5 mL of dioxane and, if necessary, 1 mL of MeOH was added to redissolve the residue and solvent was again removed on the rotary evaporator and in the vacuum oven. After drying in the vacuum oven overnight, an HPLC was taken of each product. HPLC show primarily the desired product and with about 15% deblocked product product with the BOC group removed).
Step B: To each round bottom flask was added 5 mL of 4 N HC1 in dioxane. After sitting at room temperature for 2-3 hours, an HPLC was taken and was solvent removed on the rotary evaporator (bath temp 30-35 0 C) and in the vacuum oven overnight (at approximately 40 0 The HPLC of the t-butyl threonine adduct showed incomplete removal of the t-butyl group. An additional 5 mL of 4 N HCI in dioxane was added and the reaction (at room WO 98/28268 PCT/US97/22986 600 temperature) monitored by HPLC at 4 hours and approximately 20 hours.
Complete removal of the t-butyl group was observed after 20 hours. All products were pure by HPLC with only a single peak or resolved diastereomeric peaks observed except for some trace impurities in the methione case. Yields varied from 80 to 100%. Each round bottom contained approximately 150 umoles of the amino acid linked to 5-amino-7-methyl-5,7dihydro-6H-dibenz[b,d]azepin-6-one.
Step C: A stock solution of 567 mg (1.48 mmol) PP-HOBT in 8.5 mL DMF (approximately 0.175 M PP-HOBT in DMF) was-prepared and 0.81 g (0.86 mL, 150 umol) of this PP-HOBT solution was added to each of the nine round-bottom vessels containing the products from Step B. Clear solutions were obtained for all, except where the linked amino acid was alpha amino isobutyric acid. In this case, an additional 0.86 mL of DMF was added but still the mixture remained heterogeneous. The contents of each of the nine round bottoms (where n 1 to 9) were divided into four equal portions (approximately 37 umols each) and placed in vials. Stock solutions (0.1 M) of the carboxylic acids were then made up in 10% DMF/DCM. The appropriate stock solution (0.3 mL, 30 umol) was then added to each of the vials. A 0.1 M stock solution (20 mL) of EDC hydrochloride in DMF was prepared. This stock solution (0.4 mL, 40 umol) was then added to each of the vials which were then capped and put on a rotator for 12 hours. Normal SCX workup and evaporation of solvent afforded products as white solids or clear to light caramel resins. Each of these products was taken up in methanol/chloroform and divided into three tared vials, plus a vial for MS and HPLC characterization. After evaporation of solvent, the final weights in each vial were determined. Product identity was verified by ionspray mass spec and purity assessed by reverse phase HPLC.
Example C-AF Preparation of PP-HOBT WO 98/28268 PCT/US97/22986 601 To a stirred solution of 7.68g (30 mmol) sulfonyl chloride in 120 mL of dichloromethane was added dropwise, over a 10 min period, 5.04g (30 mmol) of 4-piperidino-piperidine (Aldrich, 90%) and 3.6 g (36 mmol) of triethylamine in 30 mL of dichloromethane. A mildly exothermic reaction ensued. After stirring 2 hours at room temperature, the orange solution was diluted with 100 mL of dichloromethane and washed with 10% sodium bicarbonate solution (2 x 100 mL) and brine (1 x 100 mL). After drying over sodium sulfate, the solvent was removed at reduced pressure to afford 10.7 g of crude product as a light tan solid (Rf 0.5, Silica, 10% MeOH/chloroform).
To this crude material was added 200 mL of 95% EtOH/5 MeOH followed by 60 mL of hydrazine hydrate. The mixture was refluxed for 3 hours. During the first 0.5 hour, the initially orange solution turned deep redorange before turning orange again. After refluxing for 3 hours, most of the solvent, water and hydrazine was removed at reduced pressure. To the residue was added 50 mL of EtOH and solvent removed at reduced pressure. This was repeated 2 or more times to give a tan solid which was further dried in the vacuum oven to a constant weight of 13.5 g. To the flask containing this solid was added 250 mL of water. Almost all of the solid went into solution, then a fine light yellow precipitate formed. After stirring cooled in an ice bath for two hours, the solid was collected by vacuum filtration through a sintered glass filter, and rinsed with about 20 mL of cold water. Drying in the vacuum oven at 40 0 C overnight afforded 7.3 g (63% yield) of the title compound (PP-HOBT) as an off-white crunchy powder, mp 195-200°C (dec).
Using the procedures indicated, the compounds shown in Table C-5 were prepared. Starting material 2 used in these procedures was prepared as described in General Procedure C-S.
Table Example Compound Starting Material 1 Starting Material 2 General MIS No. Procedure 7C-22 1 5-{N ,5-difluorophenylacetyl)- 3,5 -difluorophenylacetic 5-(L-methioninyl)-amino-7- C-s 524.3 L-methioninyl} -amino-7-methyl- acid methyl-S ,7-dihydro-6H- 5,7-dihydro-6H- (Aldrich) dibenz[b,dlazepin-6-one dibenz[b ,dlazepin-6-one 7C-222 5- ,5-difluorophenylacetyl)- 3, 5-difluorophenylacetic 5-(L-2-phenylglycinyl)- C-S 526.5 L-2-phenyiglycinyll-amino-7- acid amino-7-methyl-5,7methyl-S ,7-dihydro-6H- (Aldrich) dihydro-6Hdibenz[b ,djazepin-6-one dibenz[b azepin-6-one 7C-223 ,5-difluorophenylacetyl)- 3 ,5-difluorophenylacetic 5-(L-Ieucinyl)-amino-7- C-S 506.3 acid methyl-S ,7-dihydro-6Hdihydro-6H-dibenzllb,djazepin-6- (Aldrich) dibenz[b,djazepin-6-one one 7C-224 ,5-difluorophenylacetyl)- 3 ,5-difluorophenylacetic 5-(L-2-cyclohexylglycinyl)- C-S 532.3 L-2-cyclohexylglycinyl}-amino-7- acid amino-7-methyl-5 ,7methyl-5,7-dihydro-6H- (Aldrich) dihydro-6Hdibenz[b, dlazepin-6-one dibenz[b,djazepin-6-one 7C-225 5-{N ,5'-difluorophenylacetyl)- 3 ,5-difluorophenylacetic 5-(L-threoninyl)-amino-7- C-S 494.5 L-threoninyl)}-amino-7-methyl- acid methyl- 7-dihydro-6H- ,7-dihydro-6H- (Aldrich) dibenb ,djazepin-6-one dibenz[b Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 7C-226 ,5-difluorophenylacetyt)- 3 ,5-difluorophenylacetic 5-(L-alpha-(2- C-S 532.2 L-alpha-(2-thienyl)glycinyl} acid thienyl)glycinyl)-amino-7- ,7-dihydro-6H- (Aldrich) methyl- 7-dihydro-6Hdibenz[b ,dlazepin-6-one dibenz~b ,dllazepin-6-one 7C-227 5- '-(2-thiopheneacetyl)-L- 2-thiopheneacetic acid 5-(L-methioninyl)-amino-7- c-S 494.3 (Aldrich) methyl-S ,7-dihydro-6Hdihydro-6H-dibenz[b ,d]azepin-6- dibenz[b ,dlazepin-6-one one 7C-228 -(2-thiopheneacetyl)-L-2- 2-thiopheneacetic acid 5-(L-2-phenylglycinyl)- C-S 496.2 phenyiglycinyl) -amino-7-methyl- (Aldrich) amino-7-methyl-5 ,7- 5,7-dihydro-6H- d ihydro-6Hdibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-229 5-{N '-(2-thiopheneacetyD-L- 2-thiopheneacetic acid 5-(L-leucinyl)-amino-7- C-S 476.2 leucinyl }-amino-7-methyl-5 (Aldrich) methyl-S ,7-dihydro-6Hdihydro-6H-dibenz[b,djazepin-6- dibenz[b ,dlazepin-6-one one XC-230 N' -(2-thiopheneacetyl)-L-2- 2-thiopheneacetic acid 5-(L-2-cyclohexylglycinyl)- C-S 502.2 cycloliexylglycinyl}-amino-7- (Aldrich) amino-7-methyl-5,7- ,7-dihydro-6H- dihydro-6Hdibenz[b,djazepin-6-one dibenz[b,dlazepin-6-one 7C-23 1 5- {N '-(2-thiopheneacetyl)-L- 2-thiopheneacetic acid 5-(L-threoninyl)-amino-7- C-S 464.3 (Aldrich) methyl-S ,7-dihydro-6Hdihydro-6H-dibenz jb ,dlazepin-6- dibenz[b ,dlazepin-6-one one__ Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 7C-232 5-{N'-(2-thiopheneacetyl)-L- 2-thiopheneacetic acid 5-(L-alpha-(2- C-S 502.1 alpha-(2-thienyl)glycinyl} -amino- (Aldrich) thienyl)glycinyl)-amino-7- 7-methyl-S ,7-dihydro-6H- methyl-5 ,7-dihydro-6Hdibenz[b,d]azepin-6-one dibenz~b ,dlazepin-6-one 7C-233 5-{N'-(isovaleryl)-L- isovaleric acid 5-(L-methioninyl)-amino-7- C-S 454.2 methioninyl }-amino-7-methyl-5 (Aldrich) methyl-S ,7-dihydro-6Hdihiydro-6H-dibenb ,dlazepin-6- dibenz[b ,djazepin-6-one one 7C-234 5- {N '-(isovaleryl)-L-2- isovaleric acid 5-(L-2-phenylglycinyl)- C-S 456.4 phenyiglycinyll}-amino-7-methyl- (Aldrich) amino-7-methyl-5 ,7- S ,7-dihydro-6H- dihydro-6Hdibenz[b ,dlazepin-6-one dibenzlb ,dlazepin-6-one 7C-235 5-{N'-(isovaleryl)-L-leucinyl}- isovaleric acid 5-(L-leucinyl)-amino-7- C-S 436.4 amino-7-methyl-S ,7-dihydro-6H- (Aldrich) methyl-S ,7-dihydro-6Hdibenz[b,djazepin-6-one dibenz[b ,dlazepin-6-one 7C-236 5-{N'-(isovaleryl)-L-2- isovaleric acid 5-(L-2-cyclohexylglycinyl)- C-S 462.6 cyclohexyiglycinyl }-amino-7- (Aldrich) amino-7-methyl-5 ,7methyl-S ,7-dihydro-6H- dihydro-6Hdibenzfb ,djazepin-6-one dibenz[b,dlazepin-6-one 7C-237 5-{N'-(isovaleryl)-L-threoninyl}- isovaleric acid 5-(L-threoninyl)-amino-7- C-S 424.3 amino-7-methyl-S ,7-dihydro-6H-- (Aldrich) methyl-S ,7-dihydro-6Hdibenb ,dJazepin-6-one dibenz[b ,dlazepin-6-one Example Compound Starting Material 1 Starting Material 2 General MS No. _________Procedure 7C-238 5-{N'-(isovaleryl)-L-alpha-(2- isovaleric acid 5-(L-alpha-(2- C-S 462.3 thienyl)glycinyl}-amino-7-methyl- (Aldrich) thienyl)glycinyl)-amino-7- 5,7-dihydro-6H- methyl-S ,7-dihydro-6Hdibenz[b,djazepin-6-one dibenzllb,dlazepin-6-one 7C-239 5-{N'-(phenylacetyl)-L- phenylacetic acid 5-(L-methioninyl)-amino-7- C-S 488.5 methioninyl) -amino-7-methyl-5 (Aldrich) methyl-S ,7-dihydro-6Hdihydro-6H-dibenz[b ,dlazepin-6- dibenz[b ,dlazepin-6-one one 7C-240 5- -(phenylacetyl)-L-2- phenylacetic acid 5-(L-2-phenylglycinyl)- C-S 490.6 phenylglycinyl} -amino-7-methyl- (Aldrich) amino-7-methyl-5 ,7- ,7-dihydro-6H- dihydro-6Hdibenz[b,dlazepin-6-one dibenz[b,djazepin-6-one_____ 7C-24 1 N' -(phenylacetyl)-L-leucinyl}- phenylacetic acid 5-(L-leucinyl)-amino-7- C-S 470.4 ,7-dihydro-6H- (Aldrich) methyl-S ,7-dihydro-6Hdibenzb,dlazepin-6-one dibenzlb ,djazepin-6-one 7C-242 5-{N '-(phenylacetyl)-L-2- phenylacetic acid 5-(L-2-cyclohexylglycinyl)- C-S 496.3 cyclohexylglycinyll -amino-7- (Aldrich) amino-7-methyl-5 ,7- ,7-dihydro-6H- dihydro-6Hdibenz[b ,d]azepin-6-one dibenzlb ,d]azepin-6-one_____ 7C-243 5-{N'-(phenyiacetyl)-L- phenylacetic acid 5-(L-threoninyl)-amino-7- C-S 458.5 threoninyl} -amino-7-methyl-5 (Aldrich) methyl-S ,7-dihydro-6Hd ihydro-6H-dibenz[b ,dlazepin-6- dibenz[b ,dlazepin-6-one one__ Example Compound Starting Material 1 Starting Material 2 General MS No. Procedure 7C-244 5- N'-(phenylacetyl)-L-alpha-(2- phenylacetic acid 5-(L-alpha-(2- c-s 496.2 thienyl)glycinyl} -amino-7-methyl- (Aldrich) thienyl)glyciny l)-amino-7- 5,7-dihydro-6H- methyl-S ,7-dihydro-6Hdibenz[b,dljazepin-6-one dibenz[b ,dlazepin-6-one WO 98/28268 PCT/US97/22986 607 Additionally, the following procedures provide various carboxylic acid esters which can be hydrolyzed using General Procedures AC or BD below to afford the corresponding carboxylic acids. Coupling of the resulting carboxylic acids to the amines employed above using the General Procedures set forth above provides for additional compounds within the scope of this invention.
GENERAL PROCEDURE AA Reductive Amination To a solution of the arylamine in ethanol in a hydrogenation flask was added 1 equivalent of the 2-oxocarboxylic acid ester pyruvate ester), followed by 10% palladium on carbon (25 weight percent based on the arylamine). The reaction was hydrogenated at 20 psi H 2 on a Parr shaker until complete reaction was indicated by tic (30 minutes to 16 hours). The reaction mixture was then filtered through a pad of Celite 545 (available from Aldrich Chemical Company, Inc.) and stripped free of solvent on a rotary evaporator.
The crude product residue was then further purified via chromatography.
GENERAL PROCEDURE AB First Transesterification Technique A solution of 1-5 equivalents of the desired alcohol was added to 1 equivalent of sodium hydride in toluene. After off-gassing had ceased, the compound to be transesterified, dissolved in toluene, was added. After hours, the reaction was either heated to 40"C and placed under house vacuum 20 mmHg), or nitrogen was bubbled through the solution while it was heated at 90"C. The reaction was followed by tic, and when the reaction was complete the solution was cooled and quenched with water or 1M HC1, and in smaller scale reactions diluted with ethyl acetate. The organic phase was extracted with saturated aqueous NaHCO 3 then washed with saturated aqueous NaCI and dried over MgSO,. The solution was stripped free of solvent on a rotary evaporator, and the crude product residue was then further purified by WO 98/28268 PCTUS97/22986 608 chromatography. Alternatively, the reaction mixture was worked-up by evaporation of the solvents and direct chromatography of the crude mixture.
This procedure is particularly useful in the case of costly and/or high boiling alcohols.
GENERAL PROCEDURE
AC
Second Transesterification Technique The compound to be transesterified was placed in a large excess of the desired alcohol. A catalytic amount of dry NaH was added, and the reaction was followed by tic until the presence of starting material was no longer detected. The reaction was quenched with a few milliliters of 1N HC1, and after a few minutes of stirring saturated aqueous NaHCO, was added. The organic phase was washed with saturated aqueous NaCl and dried over MgSO,. The solution was stripped free of solvent on a rotary evaporator, and the crude product residue was then further purified by chromatography.
GENERAL PROCEDURE AD Third Transesterification Technique The compound to be transesterified was placed in a large excess of the desired alcohol. A catalytic amount of dry NaH was added, and the reaction was followed by tic until the presence of starting material was no longer detected. The reaction was quenched with a few milliliters of IN HCI, and after a few minutes of stirring saturated aqueous NaHCO, was added. The volume of the reaction mixture was reduced on a rotary evaporator until the excess alcohol was removed and then the remaining residue was taken up in ethyl acetate and additional water was added. The organic phase was washed with saturated aqueous NaCI and dried over MgSO,. The solution was stripped free of solvent on a rotary evaporator, and the crude product residue was then further purified by chromatography.
WO 98/28268 PCT/US97/22986 609 This procedure is particularly employed in the case of low boiling, inexpensive alcohols, miscible with water.
GENERAL PROCEDURE
AE
O-Alkylation Technique To a carboxylic acid compound (prepared, for example, by reductive amination via General Procedure AA to provide for the N-aryl amino acid ester, followed by hydrolysis via Procedure AF) in DMF was added 1.5 equivalents KCO,, followed by 1 equivalent of alkylating agent tert-butyl -bromoacetate). The reaction was stirred at room temperature for 2 hours, then was quenched with water and extracted into ethyl acetate. The organic phase was washed with saturated aqueous NaHCO,, water, and saturated aqueous NaC1, and was then dried over MgSO,. The solution was stripped free of solvent on a rotary evaporator to yield the crude product.
GENERAL PROCEDURE AF Ester Hydrolysis to Free Acid To a carboxylic ester compound (prepared, for example, by reductive amination via General Procedure AA to provide for the N-aryl amino acid ester) in a 1:1 mixture of CH 3 OH/H,O was added 2-5 equivalents of KCO,. The mixture was heated to 50°C for 0.5 to 1.5 hours until tic showed complete reaction. The reaction was cooled to room temperature and the methanol was removed on a rotary evaporator. The pH of the remaining aqueous solution was adjusted to and ethyl acetate was added to extract the product. The organic phase was then washed with saturated aqueous NaCI and dried over MgSO,.
The solution was stripped free of solvent on a rotary evaporator to yield the crude product.
GENERAL PROCEDURE AG N-Heteroarvlation of Alanine WO 98/28268 PCTIUS97/22986 610 A solution of 1.1 equivalents of L-alanine and 2 equivalents NaOH in DMSO was stirred at room temperature for 1 hour, then I equivalent of 2chlorobenzothiazole was added. The mixture was heated to 100°C for 4 hours, then cooled to room temperature and poured onto ice. The pH of the resulting aqueous solution was adjusted to and the precipitated solid was removed by filtration. This solid was then dissolved in IN NaOH and the resulting solution was filtered through a pad of Celite 545. The pH of the filtrate was adjusted to and the white precipitate was removed by filtration and washed with water to yield the crude product.
-GENERAL PROCEDURE AH EDC Coupling To a 1:1 mixture of the desired acid and alcohol in CH,C1, at OC was added 1.5 equivalents triethylamine, followed by 2.0 equivalents hydroxybenzotriazole monohydrate, then 1.25 equivalents of ethyl-3-(3dimethylamino)-propyl carbodiimide-HCl (EDC). The reaction was stirred overnight at room temperature, then transferred to a separatory funnel and washed with water, saturated aqueous NaHCO,, IN HC1, and saturated aqueous NaC1, and was then dried over MgSO,. The solution was stripped free of solvent on a rotary evaporator to yield the crude product.
GENERAL PROCEDURE AI Oxime or Amine Coupling Technique The trichlorophenyl ester (1 eq) of a carboxylic acid was stirred in DMF or THF. The oxime or amine (1.2 eq) was added and the mixture was stirred at ambient temperature for 1-4 hours. In cases where the hydrochloride salt form of an amine was used, a suitable base such as V,N-diisopropylethylamine (1.2 eq) was also added. The resulting mixture was concentrated under reduced pressure to yield a crude product which was used without purification or was purified by silica gel chromatography and/or crystallization.
WO 98/28268 PCT/US97/22986 611 GENERAL PROCEDURE AJ Alkvlation Technique The amine (1 eq), the ac-bromo ester (1.1 eq) and a suitable base (such as triethylamine) (2 eq) were stirred in chloroform. The resulting solution was heated at reflux for 4-12 hours. After cooling, the mixture was diluted with chloroform and washed with water. The organic portion was dried (sodium sulfate) and concentrated under reduced pressure. The crude product was purified by silica gel chromatography.
GENERAL PROCEDURE AK Oxime or Alcohol Coupling Technique The carboxylic acid (1 eq) was stirred in a suitable solvent (such as THF, dioxane or DMF). An alcohol or oxime (1-5 eq) was added. EDC hydrochloride (1.2 eq) and hydroxybenzotriazole hydrate (1 eq) were added. A suitable base (such as 4-methylmorpholine or triethylamine) (0-1 eq) was added.
A catalytic amount (0.1 eq) of 4-dimethylaminopyridine was added. The mixture was stirred at ambient temperature and under a dry atmosphere of nitrogen. After 20 hours, the mixture was concentrated under reduced pressure.
The resulting concentrate was partitioned between ethyl acetate and water. The organic portion was separated and washed with aqueous sodium bicarbonate and brine. The organic portion was dried (sodium sulfate) and concentrated under reduced pressure. The crude product was used without purification or was purified by silica gel chromatography and/or crystallization.
GENERAL PROCEDURE AL EDC Coupling The carboxylic acid was dissolved in methylene chloride. The amino acid (1 N-methylmorpholine (5 eq.) and hydroxybenzotriazole monohydrate (1.2 eq.) were added in sequence. A cooling bath was applied to the round bottomed flask until the solution reached 0°C. At that time, 1.2 eq. of 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) was added.
WO 98/28268 PCTIUS97/22986 612 The solution was allowed to stir overnight and come to room temperature under nitrogen pressure. The reaction mixture was worked up by washing the organic phase with saturated aqueous sodium carbonate, 0.1M citric acid, and brine before drying with sodium sulfate. The solvents were then removed to yield crude product. Pure products were obtained by flash chromatography in an appropriate solvent.
GENERAL PROCEDURE AM Triflate Displacement To a 0°C solution of iso-butyl R-(+)-lactate in CH,C1, was added 1.1 equivalents of trifluoromethanesulfonic anhydride. After stirring at room temperature for 20 min, 1.1 equivalents of 2,6-lutidine was added and stirring was continued for 10 min. This solution was then transferred to a flask containing 1 equivalent the arylamine and 1 equivalent N,Ndiisopropylethylamine in CH,C1, or CHNO, at 0°C. The reaction was held overnight at room temperature and then stripped free of solvent on a rotary evaporator. The residue was dissolved in ethyl acetate, washed with 5% citric acid, followed by saturated aqueous NaCI, dried over magnesium sulfate or sodium sulfate and then the solution was stripped free of solvent on a rotary evaporator to yield the crude product, which was then purified by chromatography.
GENERAL PROCEDURE AN BOC Removal The BOC-protected compound was added to a 1:1 mixture of CH,C1, and trifluoroacetic acid, and was stirred until tic indicated complete conversion, typically 2h. The solution was then stripped to dryness and the residue was taken up in ethyl acetate and extracted with dilute HCI. The acid reaction was neutralized and extracted with ethyl acetate. The organic phase was washed with saturated aqueous NaCI and dried over MgSO 4 The solution was stripped free of solvent on a rotary evaporator to yield the product.
WO 98/28268 PCT/US97/22986 613 GENERAL PROCEDURE
AO
Synthesis of Pyruvate Esters To a mixture of pyruvic acid (8.8 g, 0.1 mol) (Aldrich) in 100 mL of benzene was added iso-butanol (14.82 g, 0.2 mol) and a catalytic amount of p-toluenesulfonic acid. The mixture was then refluxed using a Dean Stark apparatus. After 4 hours, the reaction appeared to be complete with the isolation of 1.8 g (0.1 mol) of water. The benzene and iso-butanol were removed on a rotary evaporator. The residue (14 g, 0.1 mol), which was primarily the pyruvate iso-butyl ester by nmr ['H-Nmr (CDCl 3 5 4.0 2H), 2.5 3H), 2.0 1H), 1.0 was used without further purification. By substituting other alcohols in place of iso-butanol ethanol, isopropanol, n-butanol, benzyl alcohol and the like), other esters of pyruvic acid can be prepared in a similar manner.
GENERAL PROCEDURE AP Aromatic Nucleophilic Substitution of Fluorobenzenes A mixture of 1.82 g (10 mmol) of D,L-alanine iso-butyl ester hydrochloride, the fluorobenzene (10 mmol) and 3 g of anhydrous potassium carbonate in 10 mL of DMSO was stirred at 120 0 C for 2-5 hours. The reaction mixture was then cooled to room temperature and diluted with 100 mL of ethyl acetate. The ethyl acetate extract was washed with water dried over MgSO 4 and evaporated to dryness to afford the crude product, which was further purified by column chromatography.
GENERAL PROCEDURE AQ Fourth Transesterification Technique The ester to be transesterified was dissolved in a large excess of the alcohol and 0.3 equivalents of titanium(IV) isopropoxide (Aldrich) was added. The reaction was followed by tic until complete and then the volatiles were removed at reduced pressure. The resulting crude material was then chromatographed to obtain the desired product.
WO 98/28268 PCT/US97/22986 614 GENERAL PROCEDURE AR Synthesis on N-BOC Anilines To a solution of the aniline in THF was added dropwise 1 equivalent of ditert-butyl dicarbonate (Aldrich) in THF and then 1.5 equivalents of 10N aqueous sodium hydroxide at 0°C. After stirring at room temperature for 16 hours, or heating at 80 0 C for 3 hours, if needed, the reaction mixture was diluted with ether and washed with NaHCO3, brine, dried over sodium sulfate and potassium carbonate, concentrated at reduced pressure and chromatographed to afford the N-BOC aniline.
GENERAL PROCEDURE AS Oxime Ester Formation The trichlorophenyl ester (1 eq.) was stirred in DMF or THF. The oxime (1.2 eq.) was added and the mixture was stirred at ambient temperature for 1 to 4 hours. The resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography and/or crystallization.
Example AA Synthesis of D,L-alanine iso-butyl ester hydrochloride A mixture of 35.64 g (0.4 mol) of D,L-alanine (Aldrich), 44 mL (0.6 mol) of thionyl chloride (Aldrich) and 200 mL of iso-butanol was refluxed for hours. The volatiles were removed at reduced pressure at 90°C under reduced pressure to give the title compound as an oil, which was used without further purification.
NMR data was as follows: 'H-nmr (CDCI 3 8 8.72 (br s, 3H), 4.27 J 7.4 Hz, 1H), 3.95 (m, 2H), 1.96 1H), 1.73 J 7.2 Hz, 3H), 0.92 J 6.7 Hz, 6H).
'"C-nmr (CDCl 3 6 170.0, 72.2, 49.2, 27.5, 18.9, 16.1.
Example AB Synthesis of N-(3,4-dichlorophenyl)alanine WO 98/28268 PCT/US97/22986 615 Using the procedure set forth in U.S. Patent No. 3.598,859, the disclosure of which is incorporated herein by reference in its entirety, N-(3,4dichlorophenyl)alanine was prepared. Specifically, to a solution of 3,4dichloroaniline (1 equivalent) (Aldrich) in isopropanol (about 500 mL per mole of 3,4-dichloroaniline) is added water (about 0.06 mL per mL of isopropanol) and 2-chloropropionic acid (2 equivalents) (Aldrich). This mixture is warmed to and sodium bicarbonate (0.25 equivalents) is added in successive portions before heating under reflux for 4-5 days. After cooling, the reaction mixture is poured into water and the unreacted 3,4-dichloroaniline is removed by filtration.
The filtrate is acidified to pH 3-4 with concentrated hydrochloric acid and the resultant precipitate is filtered, washed and dried to yield the title compound, m.p. 148-149 0
C.
Alternatively, following General Procedure AF above and using N-(3,4dichlorophenyl)alanine ethyl ester (from Example Al below), the title compound was prepared.
Example AC Synthesis of Using the procedure set forth in U.S. Patent No. 3,598,859, difluorophenyl)alanine was prepared using 3,5-difluoroaniline (Aldrich) and 2chloropropionic acid (Aldrich).
Example AD Synthesis of Iso-butyl 2-bromopropionate To a mixture of iso-butanol and 1.0 equivalent of pyridine in dry diethyl ether was added dropwise 1.3 equivalents of 2-bromopropionyl bromide at 0°C.
After stirring at room temperature for 16 hours, the reaction was diluted with diethyl ether, washed with IN HC1, water, aqueous NaHCO 3 brine and dried over magnesium sulfate or sodium sulfate. Removal of the solvents at reduced pressure gave the title compound as a clear oil.
WO 98/28268 PCTIUS97/22986 616 Example AE Synthesis of N-(2-naphthyl)alanine 2 ,4,5-trichlorophenyl ester N-(2-Naphthyl)alanine methyl ester (5.0 g, 20.6 mmol) (from Example A44 below) was dissolved in dioxane (100 mL). NaOH (30 mL, IN) was added and the resulting solution was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure. The resulting solid was dissolved in water and the aqueous mixture was washed with ether. The aqueous portion was adjusted to pH 3 with IN HCI and extracted with ethyl acetate. The organic extracts were dried over magnesium sulfate or sodium sulfate and concentrated under reduced pressure to yield a white solid (4.35 g, 98%).
The resulting solid (4.35 g, 20 mmol) was dissolved in dichloromethane (300 mL). 2,4,5-Trichlorophenol (4.9 g, 25 mmol) (Aldrich) was added followed by dicyclohexylcarbodiimide (25 mL, 1M in dichloromethane) (Aldrich). After stirring for 18 hours, the mixture was filtered and concentrated to provide an oil which was purified by chromatography on silica gel using chloroform as the eluant (Rf The title compound was obtained as a thick oil which slowly crystallized.
Example Al Synthesis of N-(3,4-dichlorophenyl)alanine ethyl ester Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and ethyl pyruvate (Aldrich), the title compound was prepared as an oil. The reaction was monitored by tic on silica gel (Rf 0.4 in EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
NMR data was as follows: 'H-nmr (CDCI 3 8 7.2 1H); 6.7 6.4 (dd, 1H); 4.30 (bs, 1H); 4.2 2H); 4.1 1H); 1.5 3H); 1.3 3H).
"C-nmr (CDCl 3 6 175; 146.7; 133; 131; 121; 114.9; 112.6; 72.0; 52.4; 28.3; 19.5.
WO 98/28268 PCT/US97t22986 617
C,,H,
3 CI,NO (MW 262.14).
Example A2 Synthesis of N-( 3 -trifluoromethyl-4-chlorophenyl)alanine ethyl ester Following General Procedure AA above and using 4-chloro-3- (trifluoromethyl)aniline (Aldrich) and ethyl pyruvate (Aldrich), the title compound was prepared.
Analysis: Calc.: C, 48.74; H, 4.43; N, 4.74. Found: C, 48.48; H, 4.54; N, 4.94.
C,H,
3
F
3 CINO, (MW 295.69); mass spectroscopy 295.
Example A3 Synthesis of N-(3,5-dichlorophenyl)alanine ethyl ester Following General Procedure AA above and using (Aldrich) and ethyl pyruvate (Aldrich), the title compound was prepared.
Analysis: Calc.: C, 50.40; H, 5.00; N, 5.34. Found: C, 50.50; H, 5.06; N, 5.25.
C,,H
3 C1,NO, (MW 262.14); mass spectroscopy (MH NA.
Example A4 Synthesis of N-(3,4-difluorophenyl)alanine ethyl ester Following General Procedure AA above and using 3,4-difluoroaniline (Aldrich) and ethyl pyruvate (Aldrich), the title compound was prepared. The reaction was monitored by tic on silica gel (Rf 0.4 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using EtOAc/hexanes as the eluant).
NMR data was as follows: 'H-nmr (CDCI 3 5 7.4 1H), 6.8 1H), 6.5 1H), 4.30 (bs, 1H), 4.2 2H), 4.1 1H), 1.5 3H), 1.3 3H).
"C-nmr (CDCl 3 6 175, 146.7, 135, 132, 125, 116, 113, 72, 52, 28, 19.
C,,H,
3 F,NO, (MW 229.23); mass spectroscopy 230.
WO 98/28268 PCT/US97/22986 618 Example Synthesis of N-( 3 4 -dichlorophenyl)alanine benzyl ester Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and benzyl pyruvate (prepared by following General Procedure AO above using benzyl alcohol in place of iso-butanol), the title compound was prepared as an oil. The reaction was monitored by tic on silica gel (Rf 0.4 in EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
NMR data was as follows: 'H-nmr (CDC1,): 8 7.18 1H); 7.0 5H); 6.6 6.4 (dd, 1H); 5.1 2H); 4.30 (bs, 1H); 4.08 1H); 1.94 1H); 1.47 3H); 0.91 (d, 6H).
'C-nmr (CDC1 3 6 174.5; 146.7; 133.5; 131.3; 121.3; 120.1; 114.9; 113.6; 72.0; 60.1; 52.4; 28.3; 19.5; 19.3.
C,
6 H,,CI,NO, (MW 324.31); mass spectroscopy 325.
Example A6 Synthesis of N-(3,4-dichlorophenyl)alanine iso-butyl ester Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and iso-butyl pyruvate (prepared by following General Procedure AO above), the title compound was prepared as an oil. The reaction was monitored by tic on silica gel (Rf 0.55 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
NMR data was as follows: 'H-nmr (CDCl,): 6 7.18 1H, J=8.7 Hz), 6.66 1H, J=2.7 Hz), 6.43 (dd, 1H, J 8.7 Hz, J 2.7 Hz), 4.30 (bs, 1H), 4.08 1H, J 6.9 Hz), 1.94 (sept, 1H, J 6.7 Hz), 1.47 3H, J 6.9 Hz), 0.91 6H, J 6.6 Hz).
'C-nmr (CDC1 3 8 174.5, 146.7, 133.5, 131.3, 121.3, 114.9, 113.6, 72.0, 52.4, 28.3, 19.5, 19.3.
WO 98/28268 PCT/US97/22986 619
C,
3
HI
7
CI
2 NO, (MW 290.19); mass spectroscopy 290.
Example A7 Synthesis of N-(3,4-dichlorophenyl)alanine iso-propyl ester Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and isopropyl pyruvate (prepared by following General Procedure AO above using isopropanol in place of iso-butanol), the title compound was prepared as an oil. The reaction was monitored by tic on silica gel (Rf 0.4 in EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
NMR data was as follows: 'H-nmr 6 7.18 1H); 6.66 6.43 (dd, 1H); 4.30 (bs, 1H); 4.08 1H); 1.94 1H); 1.47 3H); 0.91 6H).
3 C-nmr (CDC1 3 6 174.5; 146.7; 133.5; 131.3; 121.3; 114.9; 113.6; 72.0; 52.4; 19.5.
CIH C1,NO, (MW 276.16); mass spectroscopy 277.
Example A8 Synthesis of N-(3,4-dichlorophenyl)alanine n-butyl ester Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and n-butyl pyruvate (prepared by following General Procedure AO above using n-butanol in place of iso-butanol), the title compound was prepared.
The reaction was monitored by tic on silica gel (Rf 0.7 in EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
NMR data was as follows: 'H-nmr (CDC1,): 8 7.18 1H); 6.66 6.43 (dd, 1H); 4.30 (bs, 1H); 4.2 2H); 4.08 1H); 1.94 1H); 1.47 4H); 0.91 3H).
3 C-nmr (CDCl 3 8 174.5; 146.7; 133.5; 131.3; 121.3; 114.9; 113.6; 72.0; 52.4; 28.3; 20.2; 19.5.
C
1 3
HI
7 CINO, (MW 290.19); mass spectroscopy (MH) 291.
WO 98/28268 PCT/US97/22986 620 Example A9 Synthesis of N-(3,4-dichlorophenyl)alanine methyl ester (R,S isomers) Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and methyl pyruvate (Aldrich), the title compound was prepared as an oil. The reaction was monitored by tic on silica gel (Rf 0.55 in EtOAc/hexanes) and purification was by flash chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
NMR data was as follows: 'H-nmr (CDCI 3 5 7.19 J 8.73 Hz, 1H), 6.66 J 2.75 Hz, 1H), 6.43 (dd, J 8.73 Hz, 2.80 Hz, 1H), 4.25 (bd, J 8.25 Hz, 1H), 4.08 1H), 3.76 3H), 1.47 J 6.90 Hz).
"1C-nmr (CDCl 3 8 174.35, 145.96, 132.87, 130.70, 120.76, 114.38, 112.90, 52.43, 51.70, 18.67.
CoHICINO, (MW 248.11); mass spectroscopy 247.
Example Synthesis of N-(3,4-dichlorophenyl)alanine cyclopentyl ester Following transesterification General Procedure AB above and using N-(3,4dichlorophenyl)alanine methyl ester (from Example A9 above) and cyclopentanol (Aldrich), the title compound was prepared as an oil. The reaction was monitored by silica gel tic (Rf 0.66 in 25% EtOAc/hexanes).
Purification was by preparative plate chromatography (silica gel using EtOAc/hexanes as the eluant).
NMR data was as follows: 'H-nmr (CDCl1): 8 7.19 1H, J 8.7 Hz), 6.66 1H, J 2.7 Hz), 6.43 (dd, 1H, J 8.7 Hz, J 2.7 Hz), 5.22 1H), 4.27 1H, J 8.1 Hz), 4.02 (quint, 1H, J 7.5 Hz), 1.74 8H), 1.43 3H, J 6.9 Hz).
WO 98/28268 PCT/US97/22986 621 3 C-nmr (CDCI 3 5 174.3, 146.7, 133.4, 131.2, 121.2, 114.9, 113.7, 78.9, 52.5, 33.2, 24.2, 24.1, 19.1.
C,
4
H,
7 CINO (MW 302.20); mass spectroscopy 301.
Example Al 1 Synthesis of N-(3,4-dichlorophenyl)alanine n-propyl ester Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and n-propyl pyruvate (prepared by following General Procedure AO above using n-propanol in place of iso-butanol), the title compound was prepared as an oil. The reaction was monitored by tic on silica gel (Rf 0.5 in EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
NMR data was as follows: 'H-nmr (CDCl,): 8 7.2 1H); 6.6 1H); 6.4 (dd, 1H); 4.30 (bs, 1H); 4.2 2H); 4.08 1H); 1.94 2H); 1.5 3H); 0.95 3H).
13C-nmr (CDCl 3 6 178; 144.7; 130.2; 120.62; 115.11; 71.82; 52.90.
C
12
H
1 sCI,NO, (MW 276.16); mass spectroscopy 277.
Example A12 Synthesis of N-(3,4-dichlorophenyl)alanine allyl ester Following transesterification General Procedure AB above and using N-(3,4dichlorophenyl)alanine methyl ester (from Example A9 above) and allyl alcohol (Aldrich), the title compound was prepared as an oil. The reaction was monitored by silica gel tic (Rf 0.62 in 25% EtOAc/hexanes). Purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
NMR data was as follows: 'H-nmr (CDC1,): 8 7.19 1H, J 8.7 Hz), 6.67 1H, J 2.8 Hz), 6.44 (dd, 1H, J 8.7 Hz, J=2.8 Hz), 5.90 1H), 5.30 2H), 4.64 2H), 4.26 1H, 4.10 1H), 1.48 3H, J 6.9 Hz).
WO 98/28268 PCT/US97/22986 622 "C-nmr (CDCl 3 5 174.1, 146.6, 133.5, 132.1, 131.3, 121.4, 119.6, 115.0, 113.6, 66.5, 52.4, 19.3.
C, H, 3 CINO (MW 274.15); mass spectroscopy 273.
Example A13 Synthesis of N-(3,4-dichlorophenyl)alanine 4-methylpentyl ester Following transesterification General Procedure AB above and using N-(3,4dichlorophenyl)alanine methyl ester (from Example A9 above) and 4- Smethylpentanol (Aldrich), the title compound was prepared as an oil. The reaction was monitored by silica gel tic (Rf 0.70 in 25% EtOAc/hexanes).
Purification was by preparative plate chromatography (silica gel using EtOAc/hexanes as the eluant).
NMR data was as follows: 'H-nmr (CDCl1): 5 7.18 1H, J 8.7 Hz), 6.66 1H, J 2.7 Hz), 6.43 (dd, 1H, J 8.7 Hz, J 2.7 Hz), 4.28 1H), 4.10 3H), 1.55 (m, 6H), 1.19 2H), 0.87 3H, J 6.6 Hz).
3 C-nmr (CDCI 3 8 174.6, 146.7, 133.4, 131.3, 121.3, 115.0, 113.6, 66.4, 52.4, 35.4, 28.2, 27.0, 23.0, 19.3.
C,
5 H,,C1,NO, (MW 318.25); mass spectroscopy 317.
Example A14 Synthesis of N-( 3 ,4-dichlorophenyl)alanine 2,2-dimethyl-1,3-dioxolane-4methyl ester Following transesterification General Procedure AB above and using N-(3,4dichlorophenyl)alanine methyl ester (from Example A9 above) and 2,2-dimethyl- 1,3-dioxolane-4-methanol (solketal) (Aldrich), the title compound was prepared as a mixture of diastereomers. The reaction was monitored by silica gel tic (Rf 0.32 in 25% EtOAc/hexanes). Purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
NMR data was as follows: WO 98/28268 PCT/US97/22986 623 'H-nmr (CDC1 3 6 7.19 I H, J =8.7 Hz), 6.66 1H, 2.7 Hz), 6.43 (dd, IlH, J =8.7 Hz, J 2.7 Hz), 4.22 (in, 6H), -3.70 (in, 1H), 1.43 (in. 9H).
3 C-nmr (CDC1 3 6 174.34, 174.32, 146.5. 133.5, 131.3, 121.5, 115.0, 113.6, 110.52, 110.51, 73.97, 73.89, 66.6, 66.01, 65.95, 52.42, 52.37, 27.3, 25.8, 19.3.
C,
5
H
19 C1 2 N0 4 (MW 348.23); mass spectroscopy 347.
Example Synthesis of N-(3,4-dichlorophenyl)alanine cyclohexylniethyl ester Following transesterification General Procedure AB above and using N-(3,4dichlorophenyl)alanine methyl ester (from Example A9 above) and cyclohexylmethanol (Aldrich), the title compound was prepared.
NMR data was as follows: 'H-nnir (CDCI,): 6 7.19 1H), 6.68 1H), 6.45 (dd, IH), 4.26 (bd, 1H), 4.10 (in. 1H1), 3.95 2H), 1.70-1.55 (mn, 6H), 1.50 3H), 1.35-0.85 (in, 3 C-nrnr (CDC1 3 6 174.58, 146.72, 133.48, 131.27, 121.34, 114.98, 113.72, 71.06, 52.52, 37.68, 30.10, 26.83, 26.17, 19.32.
C
15
H-,
1 C1,N0 2 (MW 318.25); mass spectroscopy (MHW) 317.
Example Al16 Synthesis of N-(3,4-dichlorophenyl)alanine tert-butyloxycarbonylmethyl ester Following General Procedure AE above arnd using N-(3,4dichlorophenyl)alanine (from Example AB above) and tert-butyl bromoacetate (Aldrich), the title compound was prepared as a solid. The reaction was monitored by silica gel tic (Rf 0.57 in 25% EtOAc/hexanes). Purification was by recrystallization from ethanol.
NMR data was as follows: 'H-nmr (CDCl 3 6 7.19 6.68 6.45 (dd, 1H), 4.55 (in, 2H), 4.20 (in, 2H), 1.55 3H), 1.45 9H).
WO 98/28268 PCT/US97/22986 624 3 C-nmr (CDCI 3 6 173.9, 166.9, 146.5, 133.5, 131.3, 115.1, 113.6, 83.4, 62.2, 52.2, 28.6, 19.3.
C,
5
H,,CI,NO
4 (MW 348.23); mass spectroscopy 347.
Example A17 Synthesis of N-(3,4-dichlorophenyl)leucine iso-butyl ester Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and iso-butyl 4-methyl-2-oxopentanoate (prepared by following General Procedure AO above using 4-methyl-2-oxovaleric acid (Fluka) and iso-butanol), the title compound was prepared as an oil. The reaction was monitored by tic on silica gel (Rf 0.6 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
NMR data was as follows: 'H-nmr (CDCI,): 6 7.2 1H); 6.5 1H); 6.4 (dd, 1H); 4.30 (bs, 1H); 4.08 1H); 3.8(m, 2H); 1.8 3H); 0.91 12H).
3 C-nmr (CDCl1): 8 174.5; 146.7; 133.5; 131.3; 121.3; 114.9; 113.6; 72.0; 52; 28.3; 20.1; 19.5.
C,
6
H,
3 C,NO, (MW 332.27); mass spectroscopy (MHW) 333.
Example A18 Synthesis of 2-[N-(3,4-dichlorophenyl)amino]pentanoic acid iso-butyl ester Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and iso-butyl 2-oxopentanoate (prepared by following General Procedure AO above using 2-oxovaleric acid (Fluka) and iso-butanol), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf 0.5 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
NMR data was as follows: 'H-nmr (CDC1,): 6 7.2 1H); 6.6 1H); 6.4 (dd, 1H); 4.3 1H); 3.8 3H); 1.9 6H); 1.0 3H), 0.9 6H).
WO 98/28268 PCTIUS97/22986 625 3 C-nmr (CDCI 3 178; 144.7; 130.2; 120.62; 115.11; 71.82; 52.90; 28.30; 19.53.
CisH,,CINO, (MW 318.3); mass spectroscopy (MH) 319.
Example A19 Synthesis of N-(4-cyanophenyl)alanine iso-butyl ester Following General Procedure AP above and using 4-fluorobenzonitrile (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from Example AA above), the title compound was prepared as an oil. The product was recovered by column chromatography on silica gel using 1:5 EtOAc/hexanes as the eluant.
NMR data was as follows: 'H-nmr (CDCI,): 8 7.44 J 8.8 Hz, 2H), 6.57 J 8.8 Hz, 2H), 4.74 J 8.1 Hz, 1H), 4.18 J 7.4 Hz, 1H), 3.95 2H), 1.94 1H), 1.51 J 6.9 Hz, 3H), 0.91 J 6.7 Hz, 6H).
3 C-nmr (CDC1 3 5 173.4, 149.7, 133.8, 120.1, 112.7, 99.8, 71.6, 51.2, 27.7, 18.9, 18.6.
C,
4 H,8NO, MW 246.31; mass spectroscopy 247.
Example Synthesis of N-(3-chloro-4-cyanophenyl)alanine iso-butyl ester Following General Procedure AP above and using 2-chloro-4fluorobenzonitrile (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from Example AA above), the title compound was prepared. The product was recovered by column chromatography on silica gel using 1:5 EtOAc/hexanes as the eluant.
NMR data was as follows: 'H-nmr (CDCl,): 8 7.40 J 8.5 Hz, 1H), 6.62 J 2.3 Hz, 1H), 6.48 (dd, J 2.4, 8.6 Hz, 1H), 4.90 J 7.6 Hz, 1H), 4.16 (quintet, J 7.1 Hz, 1H), 3.96 (dd, J 2.2, 6.7 Hz, 2H), 1.97 1H), 1.51 J 7.0 Hz, 3H), 0.93 J 6.7 Hz, 6H).
WO 98/28268 PCT/US97/22986 626 3 C-nmr (CDCI 3 6 173.0, 150.4, 138.3, 134.9, 117.3, 112.8, 111.3, 100.6, 71.7, 51.1, 27.7, 18.9, 18.4.
C,
4
H,
7 NO,C1 MW 280.76; mass spectroscopy 281.
Example A21 Synthesis of N-(3,4-dichloro)alanine iso-butyl ester (S isomer) Following General Procedure AM above and using 3,4-dichloroaniline (Aldrich) and iso-butyl R-(+)-lactate (Aldrich), the title compound was prepared Sas an oil. The reaction was monitored by silica gel tic (Rf 0.55 in EtOAc/hexanes). Purification was column chromatography.
NMR data was as follows: 'H-nmr (CDCI,): 6 7.19 J 8.73, 1H), 6.67 J 2.75, 1H), 6.45 (dd, J 8.73, J 2.75, 1H), 4.28 (bd, J 8.36, 1H), 4.09 (quint, 1H), 3.94 J 6.66, 2H), 1.95 (hept, J 6.71, 1H), 1.49 J 6.90, 3H), 0.92 J 6.04, 6H).
3 C-nmr (CDC13): 8 174.57, 146.67, 133.47, 131.28, 121.29, 114.93, 113.63, 71.01, 52.43, 28.30, 19.55, 19.33.
C,
3
H,
7 CI,NO, (MW 290.19); mass spectroscopy 290.
Example A22 Synthesis of N-(3,4-dichloro)alanine tetrahydrofuran-3-yl-methyl ester Following transesterification General Procedure AB above and using N-(3,4dichlorophenyl)alanine methyl ester (from Example A9 above) and tetrahydro-3furanmethanol (Aldrich), the title compound was prepared as an oil. The reaction was monitored by silica gel tic (Rf 0.33 in 25% EtOAc/hexanes).
Purification was by preparative plate chromatography (silica gel using EtOAc/hexanes as the eluant).
NMR data was as follows: 'H-nmr (CDCl): 8 7.18 1H, J 8.7 Hz), 6.65 1H, J 2.7 Hz), 6.42 (dd, 1H, J 8.7 Hz, J 2.7 Hz), 4.30 1H), 4.09 3H), 3.78 (m, WO 98/28268 PCT/US97/22986 627 3H), 3.53 1H), 2.56 1H), 1.94 1H), 1.58 1H), 1.46 3H, J 6.9 Hz).
"C-nmr (CDCI 3 6 174.5, 146.6, 133.5, 131.3, 121.4, 114.9, 113.6, 70.86, 70.83, 68.2, 67.31, 67.29, 52.4, 38.7, 29.36, 29.33, 19.2.
C,
4
H,
7 C1,NO 3 (MW 318.20); mass spectroscopy 318.
Example A23 Synthesis of N-(3,5-dichlorophenyl)alanine n-propyl ester Following General Procedure AA above and using (Aldrich) and n-propyl pyruvate (which can be prepared by following General Procedure AO above using n-propanol in place of iso-butanol), the title compound could be prepared.
Example A24 Synthesis of 2-[N-(3,4-dichlorophenyl)amino]butanoic acid iso-butyl ester Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and iso-butyl 2-oxobutanoate (prepared by following General Procedure AO above using 2-oxobutyric acid (Aldrich) and iso-butanol), the title compound was prepared as an oil. The reaction was monitored by tic on silica gel (Rf 0.3 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
NMR data was as follows: 'H-nmr (CDCI,): 6 7.2 1H); 6.6 1H); 6.4 (dd, 1H); 4.3 1H); 3.8 3H); 1.9 3H); 1.0 3H); 0.9(m, 6H).
3 C-nmr (CDCl 3 6 178; 144.7; 130.2; 120.62; 115.11; 71.82; 52.90; 28.30; 20.5; 19.53.
C,
4
H,
9 CINO, (MW 304.22); mass spectroscopy 305.
WO 98/28268 PCT/US97/22986 628 Example Synthesis of N-( 4 -chlorophenyl)alanine iso-butyl ester Following General Procedure AA above and using 4 -chloroaniline (Aldrich) and iso-butyl pyruvate (prepared by following General Procedure AO above), the title compound was prepared as an oil. The reaction was monitored by tic on silica gel (Rf 0.6 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
NMR data was as follows: H-nmr (CDCI,): 8 7.18 2H), 6.66 2H), 4.30 (bs, 1H), 4.08 (q, 1H), 1.94 (sept, 1H), 1.47 3H), 0.91 6H).
3 C-nmr (CDCl 3 8 =174.5, 146.7, 133.5, 131.3, 121.3, 114.9, 113.6, 72.0, 52.4, 28.3, 19.5, 19.3.
C,
3 H,,CINO, (MW 255.75); mass spectroscopy 256.
Example A26 Synthesis of N-(3,5-dichlorophenyl)alanine iso-butyl ester Following General Procedure AA above and using (Aldrich) and iso-butyl pyruvate (prepared by following General Procedure AO above), the title compound was prepared as an oil. The reaction was monitored by tic on silica gel (Rf 0.4 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
NMR data was as follows: 'H-nmr (CDC13): 6 7.18 2H), 6.66 1H), 4.30 (bs, 1H), 4.08 (q, 1H), 1.94 1H), 1.47 3H), 0.91 6H).
S
3 C-nmr (CDCl 3 5 175; 146.7; 133; 131; 121; 114.9; 112.6; 72.0; 52.4; 28.3; 19.5.
C,
3
H,
7 ,C1NO, (MW 290.2); mass spectroscopy 291.
WO 98/28268 PCT/US97/22986 629 Example A27 Synthesis of N-(4-ethylphenyl)alanine methyl ester A solution of 0.68 g (5 mmol) of 4 '-aminoacetophenone (Aldrich), 0.60 mL of 90% methyl pyruvate (Aldrich) and 0.05 g (0.25 mmol) of p-toluenesulfonic acid in ethanol was hydrogenated in the presence of a catalytic amount of Pd/C at from 30 to 15 psi of hydrogen for 16 hours. The catalyst was removed by filtering the reaction mixture through Celite and the solvent was evaporated to provide the crude product. The product was purified by column chromatography (silica gel using 1:9 EtOAc/hexanes as the eluant) to provide the title compound.
NMR data was as follows: 'H-nmr (CDCI,): 8 1.19 J 7.6 Hz, 3H), 1.47 J 6.8 Hz, 3H), 2.54 J 7.6 Hz, 2H), 3.74 3H), 4.04 (bs, 1H), 4.13 1H), 6.57 J Hz, 2H), 7.03 J 8.4 Hz, 2H).
3 C-nmr (CDC1 3 5 15.8, 18.0, 27.9, 52.17, 52.19, 113.5; 128.6, 134.1, 144.4, 175.3.
C,
1
H,
7 NO, MW 207.27; mass spectroscopy 208.
Example A28 Synthesis of N-(4-(1-ethoxy)ethylphenyl)alanine methyl ester Following the procedure for Example A27 above, the title compound was isolated as another reaction product by column chromatography (silica gel using 1:9 EtOAc/hexanes as the eluant).
NMR data was as follows: 'H-nmr (CDC13): 8 1.15 J 7.0 Hz, 3H), 1.40 J 6.5 Hz, 3H), 1.47 J 6.1 Hz, 3H), 3.31 J 5.1 Hz, 2H), 3.74 3H), 4.14 2H), 4.29 J 6.4 Hz, 1H), 6.57 J 8.5 Hz, 2H), 7.12 J 8.4 Hz, 2H).
3 C-nmr (CDC1 3 8 15.4, 19.0, 23.9, 51.9, 52.2, 63.4, 77.3, 113.1, 127.3, 133.6, 145.8, 175.1.
C,
4
H
2
NO
3 MW 251.33; mass spectroscopy 251.
WO 98/28268 PCT/US97/22986 630 Example A29 Synthesis of N-(3,4-dichloro)alanine 2 2 -dimethylpropyl ester (R,S isomers) Following transesterification General Procedure AQ above and using N-(3,4dichlorophenyl)alanine methyl ester (from Example A9 above) and neopentyl alcohol (Aldrich), the title compound was prepared. The reaction was monitored by silica gel tic (Rf 0.72 in 25% EtOAc/hexanes). Purification was by flash chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
NMR data was as follows: 'H-nmr (CDCI,): 6 7.19 1H, J 8.7 Hz), 6.68 1H, J 2.7 Hz), 6.45 (dd, 1H, J 8.7 Hz, J 2.7 Hz), 4.29 1H), 4.11 1H), 3.85 (m, 2H), 1.49 3H, J 6.9 Hz), 0.93 9H).
"C-nmr (CDCI 3 6 174.6, 146.7, 133.5, 131.3, 121.3, 114.9, 113.7, 75.2, 52.4, 32.0, 26.9, 19.4.
C,
4 HgCI,NO, (MW 304.22); mass spectroscopy 303.
Example Synthesis of N-(3,4-dichlorophenyl)glycine iso-butyl ester 3,4-Dichloroaniline (Aldrich) was treated with di-tert-butyl dicarbonate (Aldrich) using conventional procedures to produce the N-BOC aniline. The N- BOC aniline was treated with sodium hydride in THF and then with iso-butyl 2bromoacetate (from Example AD above) to produce the N-BOC N-(3,4dichlorophenyl)glycine iso-butyl ester. The BOC group was then removed using General Procedure AN above to afford the title compound. The reaction was monitored by tic on silica gel (Rf 0.78 in 50% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using EtOAc/hexanes as the eluant).
NMR data was as follows: 'H-nmr (CDC1,): 6 7.19 (dd, J=4.1, 4.7, 3.4, 1H); 6.65 J=2.7, 1H); 6.44 (dd, J=2.7, 4.5, 4.2, 1H): 4.4 1H): 3.97 (dd, J=3.6, 3.0, 2.3, 2H); 3.87 2H); 1.9 1H); 0.93 J=6.7, 6H).
WO 98/28268 PCT/US97/22986 631 3 C-nmr (CDCI 3 171.2, 147.0. 133.5, 131.3, 121.2, 114.5, 113.3, 72.2, 46.0, 28.2, 19.6.
C,
2 H,CINO, (MW 276); mass spectroscopy 277.
Example A31 Synthesis of N-(3,4-dichlorophenyl)alanine 2-ethylbutyl ester Following General Procedure AA above and using 3 ,4-dichloroaniline (Aldrich) and 2-ethylbutyl pyruvate (prepared by following General Procedure AO above using 2-ethylbutanol (Aldrich) in place of iso-butanol), the title -compound was prepared as an oil. The reaction was monitored by tic on silica gel (Rf 0.6 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
NMR data was as follows: 'H-nmr (CDCI,): 8 7.2 1H); 6.6 1H); 6.4 (dd, 1H); 4.2 2H); 4.1 1H); 1.5 3H); 1.4 4H); 1.0 6H).
1 'C-nmr (CDC13): 178; 144.7; 130.2; 120.62; 115.11; 70.7; 51.90; 26.3; 19.53, 18.5.
C
1 sH 2 1 CINO, (MW 318.25); mass spectroscopy 319.
Example A32 Synthesis of N-( 3 -chloro-4-iodophenyl)alanine iso-butyl ester Following General Procedure AR above and using 3-chloro-4-iodoaniline (Aldrich), N-BOC-3-chloro-4-iodoaniline was prepared. To a stirred slurry of equivalents of sodium hydride in DMF was added 1.0 equivalent of N-BOC- 3-chloro-4-iodoaniline and then 1.1 equivalents of iso-butyl 2-bromopropionate (from Example AD above) were slowly added. The reaction was heated to 100 0 C for 10 hours, cooled, diluted with dichloromethane and washed with cold 1N HC1, water and brine. The solvents were removed at reduced pressure and the residue was chromatographed to provide N-BOC-N-(3-chloro-4iodophenyl)alanine iso-butyl ester as a clear oil. Following General Procedure AN above, the BOC group was removed from N-BOC-N-(3-chloro-4- WO 98/28268 PCT/US97/22986 632 iodophenyl)alanine iso-butyl ester to provide the title compound. The BOCremoval reaction was monitored by tic on silica gel (Rf 0.58 in EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 30% EtOAc/hexanes as the eluant). The compound was further purified by chromatography on an HPLC chiral column (Chiralcel OD).
NMR data was as follows: 'H-nmr (CDCl,): 6 7.52 J=8.7, 1H); 6.72 d, J=2.7, 1H); 6.25 (dd, J=2.7, 5.9, 2.7, 1H); 4.35 J=6.6, 1H): 4.08 (quintex, J=7.2, 6.7, 1H); 3.93 (d, J=6.7, 2H): 1.94 1H); 1.47 J=6.9, 3H); 0.92 J=6.9, 6H).
"C-nmr (CDCI 3 8 174.5, 148.3, 140.7, 139.5, 114.4, 114.3, 82.6, 72.0, 52.2, 28.3, 19.6, 19.3.
C,
3 H,CIINO, (MW 381.5); mass spectroscopy 382.
Example A33 Synthesis of N-(4-azidophenyl)alanine iso-butyl ester Following General Procedure AA above and using 4-azidoaniline (Aldrich) and iso-butyl pyruvate (prepared by following General Procedure AO above), the title compound was prepared as an oil. The reaction was monitored by tic on silica gel (Rf 0.3 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
NMR data was as follows: 'H-nmr (CDCl,): 6 7.3 2H), 6.8 2H), 4.30 (bs, 1H), 4.08 1H), 1.94 (sept, 1H), 1.47 3H), 0.91 6H).
13C-nmr (CDCI 3 8 174.5, 148.7, 131.5, 130.3, 121.3, 114.9, 113.6, 72.0, 52.4, 28.3, 19.5, 19.3.
C,
3
H
8
N
4 0, (MW 262.31); mass spectroscopy 263.
Example A34 Synthesis of N-[(4-phenylcarbonyl)phenyl]alanine iso-butyl ester WO 98/28268 PCTIUS97/22986 633 Following General Procedure AA above and using 4'-aminobenzophenone (Aldrich) and iso-butyl pyruvate (prepared by following General Procedure AO above), the title compound was prepared as an oil. The reaction was monitored by tic on silica gel (Rf 0.4 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
NMR data was as follows: 'H-nmr (CDCI 3 6 7.7 2H), 7.1 5H), 6.9 2H), 4.30 (bs, 1H), 4.08 1H), 1.94 (sept, 1H), 1.47 3H), 0.91 6H).
13C-nmr (CDCI 3 8 199, 178.5, 149.7, 131.5, 130.3, 126, 121.3, 114.9, 113.6, 72.0, 52.4, 28.3, 19.5, 19.3.
C2,H, 3
NO
3 (MW 325.41); mass spectroscopy 326.
Example Synthesis of N-(3,5-difluorophenyl)alanine iso-butyl ester Following General Procedure AH above and using difluorophenyl)alanine (from Example AC above) and iso-butanol, the title compound was prepared as an oil. The reaction was monitored by tic on silica gel (Rf 0.9 in 3% methanol/methylene chloride) and purification was by preparative plate chromatography (silica gel using 3% methanol/methylene chloride as the eluant).
NMR data was as follows: 'H-nmr (CDC1,): 6 6.1 3H), 4.5 (bs, 1H), 4.1 1H), 3.95 2H), 1H), 1.5 J 7 Hz, 3H), 0.95(d, J 6 Hz, 6H).
3 C-nmr (CDC1 3 6 174.44, 166.40, 166.19, 163.16, 162.95, 149.43, 96.73, 96.60, 96.48, 96.35, 94.06, 93.72, 93.37, 72.03, 52.30, 28.29, 19.47, 19.23.
C,
3
H,
7 F,NO, (MW 290.2); mass spectroscopy 291.
Example A36 Synthesis of N-(3,4-dichlorophenyl)alanine O-acylacetamidoxime ester WO 98/28268 PCTIUS97/22986 634 Following General Procedure AK above and using N-(3,4dichlorophenyl)alanine (from Example AB above) and acetamide oxime (prepared according to the procedures described in J. Org. Chem., 46, 3953 (1981)), the title compound was prepared as a semisolid. The reaction was monitored by tic on silica gel (Rf 0.4 in ethyl acetate) and purification was by preparative plate chromatography (silica gel using ethyl acetate as the eluant).
NMR data was as follows: 'H-nmr (DMSO-d 6 8 7.27 1H), 6.81 1H) 6.4 (broad s, 2H), 6.62 1H), 6.45 1H), 4.22 1H), 1.74 3H), 1.40 3H).
ClH, 3 Cl2N 3 02 (MW 290.15); mass spectroscopy 291.
Example A37 Synthesis of N-(3,4-dichlorophenyl)alanine pyrrolyl amide Following General Procedure AL above and using N-(3,4dichlorophenyl)alanine (from Example AB above) and pyrrole (Aldrich), the title compound was prepared as an oil. The reaction was monitored by tic on silica gel (Rf 0.28 in 10% ethyl acetate/hexanes) and purification was by preparative plate chromatography (silica gel using 10% ethyl acetate/hexanes as the eluant).
NMR data was as follows: 'H-nmr (CDCI,): 6 7.36 J=2.2, 2H); 7.20 J=8.7, 1H); 6.71 (d, J=2.7, 1H); 6.5 1H); 6.38 J=2.4, 2H); 4.8 1H); 4.57 J=8.7, 1H); 1.59 J=6.8, 3H).
3 C-nmr (CDC1 3 6 171.9, 146.1, 133.6, 131.5, 121.9, 119.6, 115.4, 114.7, 113.8, 51.8, 20.2.
C,
3
H,
2 CIN,O (MW 283); mass spectroscopy 284.
Example A38 Synthesis of N-(3,4-dichlorophenyl)alanine O-acylbutyramideoxime ester Following General Procedure AI above and using N-(3,4dichlorophenyl)alanine 2,4,6-trichlorophenyl ester (prepared from N-(3,4- WO 98/28268 PCTIUS97122986 635 dichlorophenyl)alanine methyl ester (from Example A9) using essentially the same procedure as described in Example AE above) and butyramide oxime (prepared according to.the procedures described in J. Org. Chem., 46, 3953 (1981)), the title compound was prepared as a semisolid. The reaction was monitored by tic on silica gel (Rf 0.25 in 50% ethyl acetate/hexanes) and purification was by preparative plate chromatography (silica gel using 50% ethyl acetate/hexanes as the eluant).
NMR data was as follows: 'H-nmr (d 6 -DMSO): 7.27 1H), 6.83 1H) 6.38 (broad s, 2H), 6.61 1H), 6.46 1H), 4.25 1H), 2.02 2H), 1.55 2H), 1.40 (d, 3H), 0.88 3H).
C,
3 HIC1,N 3 02 (MW 318.20); mass spectroscopy 319.
Example A39 Synthesis of 2-[N-(naphth-2-yl)amino]butanoic acid ethyl ester Following General Procedure AJ above and using 2-aminonaphthalene (Aldrich) and ethyl 2-bromobutyrate (Aldrich), the title compound was prepared as a solid, m.p. 81-83 0 C. The reaction was monitored by silica gel tic (Rf in CHCl 3 Purification was by chromatography (silica gel using chloroform as the eluant).
NMR data was as follows: 'H-nmr (d 6 -DMSO): 5 7.63 2H), 7.54 (d, 1H), 7.31(t, 1H), 7.12 1H), 7.03 1H), 6.62 1H), 6.32 1H), 4.15 (m, 3H), 1.42 3H), 1.19 3H).
C,
6 Hg 1 NO, (MW 257.34); mass spectroscopy 258.
Example Synthesis of N-(2-naphthyl)alanine iso-butyl ester Following General Procedure AA above and using 2-aminonaphthalene (Aldrich) and iso-butyl pyruvate (prepared by following General Procedure AO above), the title compound was prepared as an oil. Purification was by WO 98/28268 PCT/US97/22986 636 preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
NMR data was as follows: 'H-nmr (CDCI,): 6 7.65 3H), 7.38 1H, J 6.9 Hz), 7.23 1H, J 6.9 Hz), 6.93 1H), 6.81 1H, J 2.3 Hz), 4.31 1H, J 6.9 Hz), 3.95 J 6.7 Hz, J 1.6 Hz), 1.96 (sept, 1H, J 6.7 Hz), 1.57 (d, 3H, J 6.9 Hz), 0.93 (dd, 6H, J 6.7 Hz, J 1.6 Hz).
13C-nmr (CDC1 3 6 174.6, 144.2, 134.9. 129.1, 127.8, 127.6, 126.3, 126.0, 122.3, 118.1, 105.3, 71.2, 52.0, 27.7, 18.9, 18.8.
Example A41 Synthesis of N-(2-methylquinolin-6-yl)alanine so-butyl ester Following General Procedure AA above and using 6-amino-2methylquinoline (Lancaster) and iso-butyl pyruvate (prepared by following General Procedure AO above), the title compound was prepared. The reaction was monitored by silica gel tic (Rf 0.44 in 50% EtOAc/hexanes). Purification was by flash chromatography (silica gel using 50% EtOAc/hexanes as the eluant).
NMR data was as follows: 'H-nmr (CDCI 3 8 7.90 2H), 7.10 2H), 6.66 1H, J 2.6), 4.50 (bd, 1H), 4.24 1H), 3.91 2H, J 6.6 Hz), 2.64 3H), 1.91 (sept, 1H, J 6.7 Hz), 1.52 3H, J 6.9 Hz), 0.87 6H, J 6.7 Hz).
3 C-nmr (CDC13) 175.0, 155.4, 144.6, 143.4, 134.9, 130.2, 128.4, 122.8, 121.8, 104.9, 71.8, 52.7, 28.3, 25.4, 19.5, 19.4.
C,,H,,CI,NO, (MW 286.38); mass spectroscopy 287.
Example A42 Synthesis of N-(3,4-methylenedioxyphenyl)alanine iso-butyl ester Following reductive amination General Procedure AA above and using 3,4methylenedioxyaniline (Aldrich) and methyl pyruvate (Aldrich), N-(3,4- WO 98/28268 PCT/US97/22986 637 methylenedioxyphenyl)alanine methyl ester was prepared. The methyl ester was then transesterified following General Procedure AQ above and using isobutanol to provide the title compound as an oil. The reaction was monitored by silica gel tic (Rf= 0.61 in 25% EtOAc/hexanes). Purification was by preparative plate chromatography with silica gel using 25% EtOAc/hexanes as the eluant.
NMR data was as follows: 'H-nmr (CDCI,): 5 6.63 1H, 8.3 Hz), 6.25 1H, J 2.3 Hz), 6.04 (dd, 1H, J 8.3 Hz, J 2.3 Hz), 5.83 2H), 3.96 4H), 1.92 (sept, 1H, J 6.7 Hz), 1.44 3H, J 6.9 Hz), 0.90 6H, J 6.6 Hz).
3 C-nmr (CDCl 3 6 175.4, 148.9, 142.9, 140.8, 109.2, 105.8, 101.2, 97.4, 71.6, 53.6, 28.3, 19.6, 19.5.
C,
4
H,,NO
4 (MW 265.31); mass spectroscopy 265.
Example A43 Synthesis of N-( 3 ,4-ethylenedioxyphenyl)alanine iso-butyl ester Following reductive amination General Procedure AA above and using 1,4benzodioxa-6-amine (Aldrich) and methyl pyruvate (Aldrich), N-(3,4ethylenedioxyphenyl)alanine methyl ester was prepared. The methyl ester was then transesterified following General Procedure AQ above using iso-butanol to provide the title compound. Purification was by preparative plate chromatography.
NMR data was as follows: 'H-nmr (CDCl1): 8 0.91 J 7Hz, 6H), 1.42 J 7Hz, 3H), 1.8-2.0 1H), 3.8-3.95 3H), 4.0-4.1 1H), 4.15-4.25 4H), 6.12-6.2 (m, 2H), 6.65-6.75 1H).
13C-nmr (CDCI 3 6 19.55, 19.56, 19.67, 28.3, 53.4, 64.7, 65.3, 71.7, 103.1, 108.0, 118.3, 142.1, 144.6, 175.4.
C,
5
H,INO
4 (MW 279.34); mass spectroscopy 280.
WO 98/28268 PCT/US97t22986 638 Example A44 Synthesis of N-(2-naphthyl)alanine methyl ester Following reductive amination General Procedure AA above and using 2aminonaphthalene (Aldrich) and methyl pyruvate (Aldrich), the title compound was prepared. The reaction was monitored by silica gel tic (Rf 0.50 in EtOAc/hexanes). Purification was by flash chromatography with silica gel using EtOAc/hexanes as the eluant.
NMR data was as follows: 'H-nmr (CDCI,): 8 7.65 3H), 7.48 1H), 7.25 1H), 6.91 (m, 1H), 6.79 1H), 4.31 2H), 3.76 3H), 1.55 3H).
13C-nmr (CDC1 3 6 175.66, 144.78, 135.55, 129.78, 128.47, 128.22, 126.96, 126.67, 123.01, 118.66, 105.88, 52.95, 52.51, 19.45.
C,
4 HNO, (MW 229.28); mass spectroscopy (MH 229.
Example Synthesis of N-(benzothiazol-6-yl)alanine ethyl ester To a solution of 6-aminobenzothiazole (Lancaster) in dichloromethane was added 1.2 equivalents of pyridine, followed by 1.5 equivalents of trifluoroacetic anhydride. The reaction was stirred at room temperature for 3 hours and then washed with 5% citric acid, dried over MgSO 4 and stripped free of solvent on a rotary evaporator to yield 6-trifluoroacetamidothiazole. This material was dissolved in THF and then added to a suspension of KH in THF at 0°C. A catalytic amount of 18-crown-6 was added, followed by ethyl 2-bromopropionate (Aldrich). The reaction was held at room temperature for 1 hour, and then heated to reflux for 24 hours, and then cooled to room temperature. The reaction mixture was stripped free of solvent on a rotary evaporator and the resulting residue was dissolved in ether. This solution was washed with water, saturated aqueous NaCI, and dried over MgSO 4 The solution was stripped free of solvent on a rotary evaporator and the title compound was obtained by chromatography of the residue using 5% methanol/dichloromethane (Rf 0.59) as the eluant.
WO 98/28268 PCT/US97/22986 639 NMR data was as follows: 'H-nmr (CDCI,): 6 8.69 1H), 7.90 1H, J 8.8 Hz), 7.04 1H, J 2.3 Hz), 6.84 (dd, 1H, J 8.8 Hz, J 2.4 Hz), 4.41 (bd, 1H, J 7.5 Hz), 4.20 3H), 1.53 3H, J 6.9 Hz), 1.27 3H, J 7.1 Hz).
'3C-nmr (CDCl 3 5 174.9, 150.2, 147.1, 145.6, 136.3, 124.6, 115.7, 103.5, 61.9, 52.9, 19.4, 14.8.
C 2H, 4 N,O,S (MW 250.32); mass spectroscopy (MH) 251.
Example A46 Synthesis of N-(indol-5-yl)alanine iso-butyl ester (S isomer) Following General Procedure AM and using 5-aminoindole (Aldrich) and iso-butyl R-(+)-lactate (Aldrich), the title compound was prepared as an oil.
The reaction was monitored by silica gel tic (Rf 0.46 in 33% EtOAc/hexanes).
Purification was by preparative plate chromatography with silica gel using 33% EtOAc/hexanes as the eluant.
NMR data was as follows: 'H-nmr (CDCI 3 8 8.11 (bs, 1H), 7.07 J=8.8 Hz, 1H), 6.98 J=2.8 Hz, 1H), 6.83 J=2.2 Hz, 1H), 6.61 1H), 6.32 1H), 4.18 J=6.9 Hz, 1H), 3.95 (bs, 1H), 3.87 J=6.7 Hz, 2H), 1.89 (hept, J=6.7 Hz, 1H), 1.48 (d, J=6.96 Hz, 3H), 0.86 (dd, J=6.7 Hz, J=1.6 Hz, 6H).
3 C-nmr (CDCI 3 8 176.15, 141.06, 131.28, 129.24, 125.34, 113.34, 112.53, 104.21, 102.17, 71.65, 54.28, 28.36, 19.87, 19.62.
C
1 sHo 0 N20, (MW 260.34); mass spectroscopy 261.
Example A47 Synthesis of N-(naphth-2-yl)alanine O-acylacetamidoxime ester Following General Procedure AI above using N-(naphth-2-yl)alanine 2,4,6trichlorophenyl ester (from Example AE above) and acetamide oxime (prepared according to the procedures described in J. Org. Chem., 46, 3953 (1981)), the title compound was prepared as a semisolid. The reaction was monitored by tic WO 98/28268 PCT/US97122986 640 on silica gel (Rf 0.4 in ethyl acetate) and purification was by preparative plate chromatography (silica gel using ethyl acetate as the eluant).
NMR data was as follows: 'H-nmr (d'-DMSO): 8 7.64 2H), 7.54 1H), 7.32 1H), 7.13 1H), 7.04 1H), 6.78 1H) 6.42 (broad s, 2H), 6.32 1H), 4.33 1H), 1.72 3H), 1.46 3H).
CsH,1N 3 0, (MW 271.32); mass spectroscopy: 271.
Example A48 Synthesis of N-(2-naphthyl)alanine ethyl ester Following reductive amination General Procedure AA above and using 2aminonaphthalene (Aldrich) and ethyl pyruvate (Aldrich), the title compound was prepared as a solid having a melting point of 52-56 0 C. The reaction was monitored by silica gel tlc (Rf 0.50 in 25% EtOAc/hexanes). Purification was by flash chromatography with silica gel using 25% EtOAc/hexanes as the eluant.
NMR data was as follows: 'H-nmr (CDCl,): 8 7.65 3H), 7.48 1H), 7.25 1H), 6.91 (m, 1H), 6.79 1H), 4.31 2H), 3.76 3H), 1.55 3H).
3 C-nmr (CDC1 3 6 175.66, 144.78, 135.55, 129.78, 128.47, 128.22, 126.96, 126.67, 123.01, 118.66, 105.88, 52.95, 52.51, 19.45.
C,
4 H,NO, (MW 229.28); mass spectroscopy 229.
Example A49 Synthesis of N-( 3 ,4-dichlorophenyl)alanine O-acylpropionamidoxime ester Following General Procedure AI above using N-(3,4-dichlorophenyl)alanine 2,4,6-trichlorophenyl ester (prepared from N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9) using essentially the same procedure as described in Example AE above) and propionamide oxime (prepared according to the procedures described in J. Org. Chem., 46, 3953 (1981)), the title compound was prepared as a semisolid. The reaction was monitored by tic on silica gel WO 98/28268 PCTUS97t22986 641-- (Rf 0.2 in 50% ethyl acetate/hexane) and purification was by preparative plate chromatography (silica gel using 50% ethyl acetate/hexane as the eluant).
NMR data was as follows: 'H-nmr (d"-DMSO): 6 7.27 1H), 6.83 IH), 6.64 1H), 6.47 (d, 1H), 6.38 (broad s, 2H), 4.24 1H), 2.07 2H), 1.41 3H).
3 0, (MW 304.17); mass spectroscopy 305.
Example Synthesis of N-( 4 -ethoxycarbonylphenyl)alanine iso-butyl ester (S isomer) Following General Procedure AM and using ethyl 4-aminobenzoate (Aldrich) and iso-butyl R-(+)-lactate (Aldrich), the title compound was prepared as an oil. The reaction was monitored by silica gel tic (Rf 0.21 in EtOAc/hexanes). Purification was by preparative plate thin layer chromatography using 25% EtOAc/hexanes as the eluant.
NMR data was as follows: 'H-nmr (CDCI,): 6 7.82 J 8.73 Hz, 2H), 6.51 J 8.79 Hz, 2H), 4.81 J 7.82 Hz, 1H), 4.25 J 7.14 Hz, 2H), 4.15 (quint, J 7.40 Hz, 1H), 3.87 2H), 1.87 (sept, J 6.70 Hz, 1H), 1.43 J 6.95 Hz, 3H), 1.30 J 7.14 Hz, 3H), 0.84 J 6.71 Hz, 6H).
"C-nmr (CDCl 3 6 174.5, 167.3, 151.0, 132.0, 119.9, 112.5, 71.9, 60.8, 51.9, 28.2, 19.5, 19.2, 15.0.
C,,H2 3
NO
4 (MW 293.37); mass spectroscopy 294.
Example A51 Synthesis of N-[3,5-di(trifluoromethyl)phenyl]alanine iso-butyl ester (S isomer) Following General Procedure AM and using (Aldrich) and iso-butyl R-(+)-lactate (Aldrich), the title compound was prepared as an oil. The reaction was monitored by silica gel tic (Rf 0.38 in EtOAc/hexanes). Purification was by preparative plate thin layer chromatography using 10% EtOAc/hexanes as the eluant.
WO 98/28268 PCT/US97/22986 642 NMR data was as follows: 'H-nmr (CDCl,): 6 7.13 1H), 6.91 2H), 4.97 J 8.24 Hz, 1H), 4.18 1H), 3.93 J 6.59 Hz, 2H), 1.93 (sept, J 6.71 Hz, 1H), 1.49 J 7.02 Hz, 3H), 0.89 J 6.59 Hz, 6H).
"C-nmr (CDCI 3 8 174.4, 147.9, 133.6, 133.2, 132.7, 132.3, 129.4, 125.8, 122.2, 118.6, 112.81, 112.76, 111.42, 111.37, 111.32, 111.27, 111.22, 72.2, 52.0, 32.1, 28.24, 28.17, 23.2, 19.5, 19.3, 19.2, 18.9, 14.6.
C,
5
H,
7
F
6 NO, (MW 357.30); mass spectroscopy 358.
Example A52 Synthesis of N-( 3 ,5-dimethoxyphenyl)alanine iso-butyl ester
N-(
3 ,5-dimethoxyphenyl)alanine (crude, 454 mg) (prepared according to the procedure described in U.S. Patent No. 3,598,859 using (Aldrich) and 2-chloropropionic acid (Aldrich)) was treated in dry iso-butanol mL) with 0.1 mL of chlorotrimethylsilane and the reaction mixture refluxed overnight. The excess alcohol was removed at reduced pressure and the residue dissolved in ethyl acetate. The ethyl acetate solution was washed with saturated aqueous NaHCO 3 dried with Na 2
SO
4 and the solvent removed to provide the title compound. The reaction was monitored by silica gel tic (Rf 0.3 in EtOAc/hexanes). Purification was by preparative thin layer chromatography using 20% EtOAc/hexanes as the eluant.
NMR data was as follows: 'H-nmr (CDCI 3 6 0.9 J 7, 6H), 1.47 J 7, 3H), 1.9-2.0 (m, 1H), 3.7 6H), 3.85-4.0 2H), 4.1-4.2 1H), 4.3 (brs, 1H), 5.8 2H), 5.9 1H).
13C-nmr (CDC1 3 6 19.49, 19.52, 19.54, 28.3, 52.5, 55.6, 71.7, 91.1, 92.7, 149.2, 162.3, 175.2.
C,,H,
3
NO
4 (MW 281.35).
WO 98/28268 PCT/US97/22986 643 Example A53 Synthesis of N-(2-napthyl)alanine O-acylpropionamidoxime ester Following General Procedure AS and using N-(2-naphthyl)alanine 2,4,5trichlorophenyl ester (from Example AE above) and propionamide oxime (prepared according to the procedures described in J. Org. Chem., 46, 3953 (1981)), the title compound was prepared. The reaction was monitored by silica gel tic (Rf 0.5 in EtOAc). Purification was by silica gel chromatography using 1:1 EtOAc/hexanes as the eluant.
NMR data was as follows: 'H-nmr (DMSO-d 6 6 1.03 3H), 1.45 3H).
C,,H,,N
3 0, (MW 285.35); mass spectroscopy 285.
Example A54 Synthesis of N-(2-napthyl)alanine O-acylbutyramidoxime ester Following General Procedure AS and using N-(2-naphthyl)alanine 2,4,5trichlorophenyl ester (from Example AE above) and butyramide oxime (preparedaccording to the procedures described in J. Org. Chem., 46, 3953 (1981)), the title compound was prepared as an oil. The reaction was monitored by silica gel tic (Rf 0.6 in EtOAc). Purification was by silica gel chromatography using 1:1 EtOAc/hexanes as the eluant.
NMR data was as follows: 'H-nmr (DMSO-d): 8 0.86 3H), 1.46 3H).
C,
7 H2,N 3 02 (MW 299.37); mass spectroscopy 299.
Example Synthesis of N-(2-napthyl)alanine O-acylisovaleramidoxime ester Following General Procedure AS and using N-(2-naphthyl)alanine 2,4,5trichlorophenyl ester (from Example AE above) and isovaleramide oxime (prepared according to the procedures described in J. Org. Chem., 46, 3953 (1981)), the title compound was prepared as an oil. The reaction was monitored WO 98/28268 PCT/US97/22986 -644by silica gel tic (Rf 0.3 in 1:1 EtOAc/hexanes). Purification was by silica gel chromatography using 1:1 EtOAc/hexanes as the eluant.
NMR data was as follows: 'H-nmr (DMSO-d): 8 0.86 3H), 1.45 3H).
C,
1
H,
3
N
3 0O (MW 313.40); mass spectroscopy 313.
Example A56 Synthesis of N-(2-napthyl)alanine O-acylbenzamidoxime ester Following General Procedure AS and using N-(2-naphthyl)alanine 2,4,5trichlorophenyl ester (from Example AE above) and benzamide oxime (prepared according to the procedures described in J. Org. Chem., 46, 3953 (1981)), the title compound was prepared as an oil. The reaction was monitored by silica gel tic (Rf 0.3 in 1:1 EtOAc/hexanes). Purification was by silica gel chromatography using 1:1 EtOAc/hexanes as the eluant.
NMR data was as follows: 'H-nmr (DMSO-d): 8 4.42 1H), 1.53 3H).
C2 0
H
19
N
3 0 2 (MW 333.39); mass spectroscopy 333.
Example A57 Synthesis of N-(2-napthyl)alanine O-acylcyclopropanecarboxamidoxime ester Following General Procedure AS and using N-(2-naphthyl)alanine 2,4,5trichlorophenyl ester (from Example AE above) and cyclopropanecarboxamide oxime (prepared according to the procedures described in J. Org. Chem., 46, 3953 (1981)), the title compound was prepared as an oil. The reaction was monitored by silica gel tic (Rf 0.3 in 1:1 EtOAc/hexanes). Purification was by silica gel chromatography using 1:1 EtOAc/hexanes as the eluant.
NMR data was as follows: 'H-nmr (DMSO-d 6 8 0.85 4H), 1.43 3H).
C,
1 HiN 3 0, (MW 297.36); mass spectroscopy (MH 297.
WO 98/28268 PCT/US9722986 645 Example A58 Synthesis of N-(2-napthyl)alanine O-acylcyclopropylacetamidoxime ester Following General Procedure AS and using N-(2-naphthyl)alanine 2,4,5trichlorophenyl ester (from Example AE above) and cyclopropylacetamide oxime (prepared according to the procedures described in J. Org. Chem., 46, 3953 (1981)), the title compound was prepared as an oil. The reaction was monitored by silica gel tic (Rf 0.3 in 1:1 EtOAc/hexanes). Purification was by silica gel chromatography using 1:1 EtOAc/hexanes as the eluant.
NMR data was as follows: 'H-nmr (DMSO-d,): 6 1.43 3H), 1.91 2H).
C,
8 H2, 1
N
3 0 (MW 311.39); mass spectroscopy 311.
Example A59 Synthesis of N-(2-napthyl)alanine O-acylcyclopentanecarboxamidoxime ester Following General Procedure AS and using N-(2-naphthyl)alanine 2,4,5trichlorophenyl ester (from Example AE above) and cyclopentanecarboxamide oxime (prepared according to the procedures described in J. Org. Chem., 46, 3953 (1981)), the title compound was prepared as an oil. The reaction was monitored by silica gel tic (Rf 0.3 in 1:1 EtOAc/hexanes). Purification was by silica gel chromatography using 1:1 EtOAc/hexanes as the eluant.
NMR data was as follows: 'H-nmr (DMSO-d): 6 1.43 3H), 2.43 1H).
C,
7
H,,N
3 02 (MW 297.36).
GENERAL PROCEDURE BA Coupling of with H,NCH(R)C(O)XR 3 To a stirred solution of (D,L)-alanine iso-butyl ester hydrochloride (from Example BB below) (4.6 mmol) in 5 mL of pyridine was added 4.6 mmol of an acid chloride. Precipitation occurred immediately. The mixture was stirred for WO 98/28268 PCT/US97/22986 646 h, diluted with 100 mL of diethyl ether, washed with 10% HCI three times, brine once, 20% potassium carbonate once and brine once. The solution was dried over magnesium sulfate, filtered, and evaporated at reduced pressure to yield the product. Other amino acid esters may also be employed in this procedure.
GENERAL PROCEDURE
BB
Coupling of with H 2
NCH(R)C(O)XR
3 A solution of the acid (3.3 mmol) and CDI in 20 mL THF was stirred for 2 h. L-alanine iso-butyl ester hydrochloride (from Example BB below) (3.6 mmol) was added, followed by 1.5 mL (10.8 mmol) of triethylamine. The reaction mixture was stirred overnight. The reaction mixture was diluted with 100 mL of diethyl ether, washed with 10% HCI three times, brine once, potassium carbonate once and brine once. The solution was dried over magnesium sulfate, filtered, and evaporated at reduced pressure to yield the product. Other amino acid esters may also be employed in this procedure.
GENERAL PROCEDURE
BC
Esterification of R'C(X')(X")C(O)NHCH(R 2 )C(O)OH With HOR 3 To a stirred solution of phenylacetylvaline (1.6470 g, 7.0 mmol) in 20 mL THF was added CDI (1.05 g, 6.5 mmol) and the mixture was stirred for 1.5 h.
2-Methylbutanol (0.53 g, 6 mmol) was added the mixture, followed by addition of NaH (0.16 g, 6.5 mmol). Bubbling occurred immediately. The reaction mixture was stirred overnight. The reaction mixture was diluted with 100 mL of diethyl ether, washed with 10% HCI three times, brine once, 20% potassium carbonate once and brine once. The solution was dried over magnesium sulfate, filtered, and evaporated at reduced pressure to yield the product. Other N-acyl amino acids and alcohols may also be employed in this procedure.
GENERAL PROCEDURE
BD
Ester Hydrolysis to the Free Acid WO 98/28268 PCT/US97/22986 647 Ester hydrolysis to the free acid was conducted by conventional methods.
Below are two examples of such conventional de-esterification methods.
To the ester in a 1:1 mixture of CH,OH/H,O was added 2-5 equivalents of K,CO,. The mixture was heated to about 50 0 C for about 0.5 to 1.5 hours until tic showed complete reaction. The reaction was cooled to room temperature and the methanol was removed at reduced pressure. The pH of the remaining aqueous solution was adjusted to about 2, and ethyl acetate was added to extract the product. The organic phase was then washed with saturated aqueous NaCI and dried over MgSO,. The solution was stripped free of solvent at reduced pressure to yield the product.
The amino acid ester was dissolved in dioxane/water to which was added LiOH eq.) that was dissolved in water such that the total solvent after addition was about 2:1 dioxane:water. The reaction mixture was stirred until reaction completion and the dioxane was removed under reduced pressure. The residue was diluted with EtOAc, the layers were separated and the aqueous layer acidified to pH 2. The aqueous layer was back extracted with EtOAc, the combined organics were dried over Na,SO 4 and the solvent was removed under reduced pressure after filtration. The residue was purified by conventional methods recrystallization).
The following exemplifies this later example. The methyl ester of 3-NO 2 'phenylacetyl alanine 9.27 g (0.0348 mols) was dissolved in 60 mL dioxane and 15 mL of H,O and adding LiOH (3.06 g, 0.0731 mol) that has been dissolved in mL of HO. After stirring for 4 hours, the dioxane was removed under reduced pressure and the residue diluted with EtOAc, the layers were separated and the aqueous layer acidified to pH 2. The aqueous layer was back extracted with EtOAc (4 X 100 mL), the combined organics were dried over NaSO, and the solvent was removed under reduced pressure after filtration. The residue was recrystallized from EtOAc/isooctane giving 7.5 g of 3- WO 98/28268 PCT/US97/22986 648 nitrophenylacetyl alanine. C,,H,2N,0 5 requires C 52.38, H 4.80, and N 11.11. Analysis found C 52.54, H 4.85, and N 11.08. 3 29.9 589 nm.
GENERAL PROCEDURE BE Low Temperature BOP Coupling of Acid and Alcohol A solution of methylene chloride containing the carboxylic acid (100M%) and N-methyl morpholine (150 was cooled to -20°C under nitrogen. BOP (105 was added in one portion and the reaction mixture was maintained at -20 0 C for 15 minutes. The corresponding alcohol (120 was added and the reaction mixture was allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was then poured into water and extracted with ethyl acetate The combined ethyl acetate portions were backwashed with saturated aqueous citric acid saturated aqueous sodium bicarbonate (2x), brine dried over anhydrous magnesium sulfate or sodium sulfate and the solvent removed under reduced pressure to yield the crude product.
GENERAL PROCEDURE BF EDC Coupling of Acid and Amine The acid derivative was dissolved in methylene chloride. The amine (1 N-methylmorpholine (5 and hydroxybenzotriazole monohydrate (1.2 eq.) were added in sequence. The reaction was cooled to about 0°C and then 1.2 eq. of 1-( 3 -dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added. The solution was allowed to stir overnight and come to room temperature under N: pressure. The reaction mix was worked up by washing the solution with saturated, aqueous NaCO,, 0.1M citric acid, and brine before drying with NaSO, and removal of solvents to yield crude product. Pure products were obtained by flash chromatography in an appropriate solvent.
GENERAL PROCEDURE BG EDC Coupling of Acid and Amine WO 98/28268 PCT/US97/22986 649 A round bottom flask was charged with carboxylic acid (1.0 hydroxybenzotriazole hydrate (1.1 eq.) and amine (1.0 eq.) in THF under nitrogen atmosphere. An appropriate amount (1.1 eq. for free amines and 2.2 eq. for hydrochloride amine salts) of base, such as Hunig's base was added to the well stirred mixture followed by EDC (1.1 After stirring from 4 to 17 hours at room temperature the solvent was removed at reduced pressure, the residue taken up in EtOAc (or similar solvent)/water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, IN HCI, brine and dried over anhydrous sodium sulfate. In some cases, the isolated product was analytically pure at this stage while, in other cases, purification via chromatography and/or recrystallization was required prior to biological evaluation.
GENERAL PROCEDURE BH Coupling of with HNCH(R 2
)C(O)XR
An excess of oxalyl chloride in dichloromethane was added to the acid derivative together with one drop of DMF. The resulting mixture was stirred for about 2 hours or until bubbling ceases. The solvent was then removed under reduced pressure and rediluted with dry methylene chloride. To the resulting solution was added about 1.1 eq. of the appropriate amino acid ester and triethylamine (1.1 eq. in methylene chloride). The system was stirred at room temperature for 2 hours and then the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with IN HCI followed by IN NaOH. The organic layer was dried over anhydrous soldium sulfate, filtered and the solvent removed under reduced pressure to provide for the desired product.
GENERAL PROCEDURE BI P-EPC coupling P-EPC coupling employs an amino acid ester and a substituted acetic acid compound. The acetic acid derivative is well known in the art and is typically WO 98/28268 PCTIUS97/22986 650 commercially available. The amino acid ester is prepared by conventional methods from the known and typically commercially available N-BOC amino acid as described in GENERAL PROCEDURE BJ below.
Specifically, the appropriate amino ester free base (0.0346 mmols) and substituted phenylacetic acid (0.069 mmols) were dissolved in 2.0 mL CHC13 (EtOH free), treated with 150 mg of P-EPC (0.87 meq./g) and the reaction was mixed for 4 days at 23°C. The reaction was filtered through a plug of cotton, rinsed with 2.0 mL of CHC1 3 and the filtrate evaporated under a stream of nitrogen. The purity of each sample was determined by 'H NMR and ranged from 50% to Between 8.0 and 15.0 mg of final product was obtained from each reaction and was tested without additional purification.
GENERAL PROCEDURE BJ Synthesis of Amino Acid Esters From the Corresponding N-BOC Amino Acid A. Esterification of the Acid.
The N-BOC amino acid was dissolved in dioxane and treated with an excess of alcohol 1.5 eq.) and catalytic DMAP (100 mg) at 0 C. Stirring was continued until reaction completion whereupon the product was recovered by conventional methods.
B. Removal of N-BOC Group.
The N-BOC protected amino acid was dissolved in methylene chloride (0.05M) and treated with 10 eq. of TFA at room temperature under a nitrogen atmosphere. The reaction was monitored by tic until starting material was consumed usually within 1-5 hours. An additional 10 eq. of TFA was added to the reaction if the starting material was still present after 5 hours. The reaction was carefully neutralized with NaCO 3 separated, the organic layer washed with brine and dried over anhydrous Na,SO 4 The crude amine was then used without purification.
WO 98/28268 PCT/US97/22986 651 Specific exemplification of these procedures are as follows: 1. Racemic (+/-)-N-BOC-a-amino butyric acid (Aldrich) (9.29 g, 0.0457 mol) was dissolved in 100 mL of dioxane and treated with iso-butyl alcohol (6.26 mL, 0.0686 mol), EDC (8.72 g, 0.0457) and catalytic DMAP (100 mg) at 0 C. After stirring for 17 hours, the organics were evaporated at reduced pressure, the residue diluted with EtOAc washed with NaHCO 3 brine and dried over Na 2
SO
4 Evaporation yields 8.42 g of an oil. C 13 requires: C 60.21, H 9.72, and N 5.40. Anal found: C 59.91, H 9.89, and N 5.67.
The above N-BOC amino acid ester (8.00 g, 0.032 mol) was deprotected as above giving 3.12 g of the free base as a colorless oil which solidifies upon standing.
2. L-N-BOC-alanine (Aldrich) (8.97 g, 0.047 mol) was dissolved in 100 mL of CHC1 2 iso-butyl alcohol (21.9 mL, 0.238 mol) and treated with DMAP (100 mg) and EDC (10.0 g, 0.52 mol) at OC. The mixture was stirred for 17 hours, diluted with H 2 O, washed with 1.0 N HCI, NaHCO 3 then brine and the organics were dried over NaSO 4 Filtration and evaporation yields 11.8 g (quantitative) of L-N-BOC alanine iso-butyl ester which is contaminated with a small amount of solvent. A sample was vacuum dried for analytical analysis. C 12
H
23
NO
4 requires: C 58.79, H 9.38, and N 5.71. Anal found: C 58.73, H 9.55, and N 5.96.
The above N-BOC amino acid ester (11.8 g, 0.0481 mol) was deprotected as above. The free base was converted to the corresponding HC1 salt using saturated HCI (g)/EtOAc to give L-N-alanine iso-butyl ester hydrochloride.
Obtained 4.2 g of a colorless solid. C 7 HisNO 2 HC1 requires: C 46.28, H 8.88, and N 7.71. Anal found: C 46.01, H 8.85, and N 7.68.
WO 98/28268 PCTIUS97/22986 652 GENERAL PROCEDURE BK Methyl ester formation from amino acids The amino acid (amino acid or amino acid hydrochloride) is suspended in methanol and chilled to 0°C. HCI gas is bubbled through this solution for minutes. The reaction is allowed to warm to room temperature then stirred for 4 hours. The solvents are then removed at reduced pressure to afford the desired amino acid methyl ester hydrochloride. This product is usually used without further purification.
-Example
BA
Synthesis of free and polymer bound PEPC N-ethyl-N'-3-(l-pvrrolidinvl)propvlurea To a solution of 27.7 g (0.39 mol) ethyl isocyanate in 250 mL chloroform was added 50 g (0.39 mol) 3-(1-pyrrolidinyl)propylamine dropwise with cooling. Once the addition was complete, the cooling bath was removed and the reaction mixture stirred at room temperature for 4 hours. The reaction mixture was then concentrated under reduced pressure to give 74.5 g (96.4%) of the desired urea as a clear oil.
1-(3-(1-pvrrolidinvl)propvl)-3-ethylcarbodiimide
(P-EPC)
To a solution of 31.0 g (0.156 mol) N-ethyl-N'-3-(1-pyrrolidinyl)propylurea in 500 mL dichloromethane was added 62.6 g (0.62 mol) triethylamine and the solution was cooled to 0°C. To this solution were then added 59.17 g (0.31 mol) 4-toluenesulfonyl chloride in 400 mL dichloromethane dropwise at such a rate as to maintain the reaction at 0-5°C. After the addition was complete, the reaction mixture was warmed to room temperature and then heated to reflux for 4 hours. After cooling to room temperature, the reaction mixture was washed with saturated aqueous potassium carbonate (3 x 150 mL).
The aqueous phases were combined and extracted with dichloromethane. All WO 98/28268 PCT/US97/22986 653 organic phases were combined and concentrated under reduced pressure. The resultant orange slurry was suspended in 250 mL diethyl ether and the solution decanted off from the solid. The slurry/decantation process was repeated 3 more times. The ether solutions were combined and concentrated under reduced pressure to give 18.9 g of the desired product as a crude orange oil. A portion of the oil was distilled under vacuum to give a colorless oil distilling at 78-82*C (0.4 mm Hg).
Preparation of a polymer supported form of 1-(3-(1-pvrrolidinvl)propyl)-3ethylcarbodiimide (P-EPC) A suspension of 8.75 g (48.3 mmol) 1-(3-(1-pyrrolidin-yl)propyl)-3ethylcarbodiimide and 24.17 g (24.17 mmol) Merrifield's resin crosslinked, 200-400 mesh, chloromethylated styrene/divinylbenzene copolymer, 1 meq. Cl/g) in dimethylformamide was heated at 100°C for 2 days. The reaction was cooled and filtered and the resulting resin washed sequentially with 1L DMF, 1L THF and 1L diethyl ether. The remaining resin was then dried under vacuum for 18 hours.
Example BB Preparation of alanine iso-butyl ester hydrochloride A mixture of 35.64 g (0.4 mol) of (D,L)-alanine (Aldrich) (or L-alanine (Aldrich)); 44 mL (0.6 mol) of thionyl chloride (Aldrich) and 200 mL of isobutanol was refluxed for 1.5 hours and the volatiles were removed completely on a rotavapor of 90 0 C under reduced pressure to give alanine iso-butyl ester hydrochloride (or L-alanine iso-butyl ester hydrochloride), which was pure enough to be used for further transformations.
Example BC Preparation of 3,5-dichlorophenylacetic acid To a solution of 3.5 g of 3,5-dichlorobenzyl alcohol (Aldrich) in 75 mL of dichloromethane at 0 C was added 1.8 mL of methane sulfonylchloride WO 98/28268 PCTIUS97/2296 654 followed by 3.5 mL of triethylamine added dropwise. After 2 hours the solution was diluted to 150 mL with dichloromethane, washed with 3N HCI, saturated aqueous NaHCO 3 dried with NaSO, and the solvents removed to yield the desired 3,5-dichlorobenzyl methanesulfonate as a yellow oil that was used without purification.
The crude sulfonate was dissolved in 50 mL of DMF at 0°C and then 3 g of KCN was added. After 2 hours an additional 50 mL of DMF was added and the solution was stirred for 16 hours. The red solution was diluted with 1 L of H,O and acidified to pH 3 with 3N HCI. The aqueous solution was extracted with dichloromethane. The combined organics were washed with 3N HC1, dried with NaSO, and the solvents removed at reduced pressure to yield crude which was used without purification.
The nitrile was added to a mixture of 40 mL of concentrated sulfuric acid and 50 mL H 2 0 and heated to reflux for 48 hours, cooled to room temperature and stirred for 48 hours. The reaction was diluted into 1 L of crushed ice, warmed to toom temperature and extracted with 2 x 200 mL of dichloromethane and 2 x 200 mL of ethylacetate. Both sets of organics were combined and washed with saturated aqueous NaHCO 3 The NaHCO 3 fractions were combined and acidified to pH 1 with 3N HC1. The white solid was too fine to filter and was extracted out with 2 X 200 mL of dichloromethane. The combined organics were dried with Na 2
SO
4 and the solvents removed at reduced presure to yield crude 3,5-dichlorophenylacetic acid as a white solid. The solid was slurried with hexane and filtered to get 1.75g of white solid.
NMR (CDCI 3 (in ppm) 3.61 2H), 7.19 7.30 1H) Example BD Synthesis of N-(3-chlorophenylacetyl)alanine The title compound was prepared using L-alanine (Nova Biochem) and 3chlorophenyl acetic acid (Aldrich) by following General Procedures BF or BG, followed by hydrolysis using General Procedure BD.
L WO 98/28268 PCT/US97/22986 655 Example B1 Synthesis of N-(phenylacetyl)-D,L-alanine iso-butyl ester Following General Procedure BA above and using phenylacetyl chloride (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by extraction with Et 2 O followed by washes with aqueous K 2
CO
3 and aqueous HCI.
NMR data was as follows: 'H-nmr (CDC1): 6 7.23-7.36 5H), 6.18 1H), 4.58 J 7.3 Hz, 1H), 3.87 2H), 3.57 2H), 1.90 1H), 1.34 J= 7.2 Hz, 3H), 0.89 J 6.8 Hz, 6H).
3 C-nmr (CDCI,): 6 172.7, 170.3, 134.5, 129.2, 128.8, 127.2, 71.3, 48.1, 43.4, 27.5, 18.8, 18.3.
C,
5 H,,N0 3 (MW 263.34; Mass Spectroscopy (MHW 264)) Example B2 Synthesis of N-(3-phenylpropionyl)-D,L-alanine iso-butyl ester Following General Procedure BA above and using 3-phenylpropionyl chloride (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of from 51 0 -54°C. The reaction was monitored by tic on silica gel and purification was by extraction with EtzO followed by washes with aqueous KC0 3 and aqueous HC1.
NMR data was as follows: 'H-nmr (CDC1,): 6 7.25 2H), 7.19 3H), 6.28 J= 7.2 Hz, 1H), 4.58 (quint., J= 7.2 Hz, 1H), 3.89 2H), 2.95 J= 7.7 Hz, 2H), 2.50 (m, 2H), 1.92 1H), 1.33 J 7.1 Hz, 3H), 0.91 J 6.7 Hz, 6H).
13C-nmr (CDC1 3 6 173.0, 171.5, 140.6, 128.3, 128.1, 126.0, 71.2, 47.8, 37.9, 31.4, 27.5, 18.79, 18.77, 18.3.
WO 98/28268 PCT/US97/22986 656
C,
6
H,
3
NO
3 (MW 277.37, Mass Spectroscopy (MH' 278)) Example B3 Synthesis of N-(3-methylpentanoyl)-L-alanine iso-butyl ester Following General Procedure BB and using 3-methylpentanoic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as an oil. The reaction was monitored by tic on silica gel and purification was by extraction with Et,O followed by washes with aqueous KCO 3 and aqueous HC1.
NMR data was as follows: 'H-nmr (CDC1,): 8 6.08 J= 5.9 Hz, 1H), 4.62 (quint., J= 7.3 Hz, 1H), 3.92 2H), 2.22 1H), 1.84-2.00 3H), 1.40 J= 7.2 Hz, 3H), 1.35 1H), 1.20 1H), 0.85-0.96 12H).
13C-nmr (CDC13): 6 173.3, 172.1, 71.4, 47.9, 43.9, 32.3, 29.38, 29.35, 27.6, 19.10, 19.06, 18.93, 18.91, 18.72, 18.67, 11.3.
C,
13
HNO
3 (MW 243.35, Mass Spectroscopy (MH' 244)) Example B4 Synthesis of N-[(4-chlorophenyl)acetyl]-L-alanine iso-butyl ester Following General Procedure BB and using 4-chlorophenylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 111°- 113 0 C. The reaction was monitored by tic on silica gel and purification was by extraction with Et,O followed by washes with aqueous KCO 3 and aqueous HC1.
NMR data was as follows: 'H-nmr (CDC1,): 6 7.30 J= 8.2 Hz, 2H), 7.21 J= 8.3 Hz, 2H), 6.18 J= 5.5 Hz, 1H), 4.57 (quint., J= 7.2 Hz, 1H), 3.88 2H), 3.53 (s, 2H), 1.91 1H), 1.36 J= 7.1 Hz, 3H), 0.90 J= 6.8 Hz, 6H).
"C-nmr (CDCI 3 6 172.8, 169.8, 133.1, 133.0, 130.6, 128.9, 71.4, 48.2, 42.6, 27.6, 18.85, 18.82, 18.4.
WO 98/28268 PCT/US97/22986 657
C,
15 HoNO 3 CI (MW 297.78, Mass Spectroscopy (MH' 298)) Example Synthesis of 3 4 -dichlorophenyl)acetyl]-L-alanine iso-butyl ester Following General Procedure BB and using 3 4 -dichlorophenylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 81 0 -83°C.
The reaction was monitored by tic on silica gel and purification was by extraction with Et,O followed by washes with aqueous KCO 3 and aqueous HC1.
NMR data was as follows: 'H-nmr (CDCl,): 6 0.90 J= 6.8 Hz, 6H), 1.38 J= 7.1 Hz, 3H), 1.91 1H), 3.50 2H), 3.90 2H), 4.57 (quint., J= 7.1 Hz, 1H), 6.31 (d, J= 4.9 Hz, 1H),7.12 1H), 7.38 2H).
3 C-nmr (CDCl 3 8 18.4, 18.8, 18.9, 27.6, 42.2, 48.3, 71.5, 128.6, 130.6, 131.2, 131.3, 132.6, 134.7, 169.2, 172.8.
CsH 19
NO
3 C1, (MW 332.23, Mass Spectroscopy (MH' 332)) Example B6 Synthesis of 4 -methylphenyl)acetyl]-D,L-alanine iso-butyl ester Following General Procedure BB and using 4-methylphenylacetic acid (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 102 0 -104°C. The reaction was monitored by tic on silica gel (Rf =0.6 in 33% ethyl acetate/hexanes) and purification was by extraction with EtO followed by washes with aqueous KCO 3 and aqueous HC1.
NMR data was as follows: 'H-nmr (CDCI,): 8 0.90 J 6.7 Hz, 6H), 1.35 J= 7.2 Hz, 3H), 1.91 1H), 2.34 3H), 3.55 2H), 3.88 2H), 4.58 1H), 6.05 (bd, 1H), 7.16 4H).
WO 98/28268 PCT/US97/22986 658 3 C-nmr (CDC1 3 8 18.5, 18.85, 18.87, 21.0, 27.6, 43.1, 48.1, 71.3, 129.2, 129.6, 131.3, 136.9, 170.6, 172.8.
C,
6 H23NO 3 (MW 277.37, Mass Spectroscopy (MH' 278)) Example B7 Synthesis of N-[(3-pyridyl)acetyll-D,L-alanine iso-butyl ester Following General Procedure BF and using 3-pyridylacetic acid hydrochloride (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 62 0 -64 0 C. The reaction was monitored by tic on silica gel (Rf 0.48 10% methanol/dichloromethane) and purification was by silica gel chromatography.
NMR data was as follows: 'H-nmr (CDCI,): 6 8.40 J= 2.8, 2H); 7.6 1H): 7.16 2H); (quint., J= 7.2, 7.2, 1H); 3.8 2H); 3.48 2H); 1.8 1H); 1.30 J 7.2, 3H); 0.81 J= 6.7, 6H).
3 C-nmr (CDC13): 6 173.4, 170.1, 150.6, 148.8, 137.4, 131.4, 124.1, 71.9, 48.9, 40.6, 28.1, 19.5, 19.4, 18.6.
C,
4
H
20 N,0 3 (MW 264, Mass Spectroscopy (MH' 265)) Example B8 Synthesis of N-[(1-naphthyl)acetyl]-L-alanine iso-butyl ester Following General Procedure BB and using 1-naphthylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 69 0 -73 0 C. The reaction was monitored by tic on silica gel and purification was by extraction with Et 2 O followed by washes with aqueous KCO 3 and aqueous HCI.
NMR data was as follows: 'H-nmr (CDCI): 8 0.83 6H), 1.25 J= 7.1 Hz, 3H), 1.81 1H), 3.79 2H), 4.04 (2s, 2H), 4.57 (quint., J= 7.3 Hz, 1H), 5.99 J= 7.1 Hz, 1H), 7.44 2H), 7.53 2H), 7.85 2H), 7.98 1H).
WO 98/28268 PCT/US97/22986 659 "C-nmr (CDCI 3 8 18.2, 18.81, 18.83, 27.5, 41.5, 48.2, 71.3, 123.7, 125.6, 126.1, 126.6, 128.2, 128.5, 128.7, 130.7, 132.0, 133.9, 170.3, 172.5.
C,
9
H
2 3
NO
3 (MW 313.40, Mass Spectroscopy (MH' 314)) Example B9 Synthesis of N-[(2-naphthyl)acetyl]-L-alanine iso-butyl ester Following General Procedure BB and using 2-naphthylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 128 0 -129°C. The -reaction was monitored by tic on silica gel and purification was by extraction with Et,O followed by washes with aqueous KCO3 and aqueous HC1.
NMR data was as follows: 'H-nmr (CDCI,): 8 0.86 6H), 1.35 J= 7.1 Hz, 3H), 1.78 1H), 3.76 2H), 3.87 2H), 4.62 (quint., J= 7.2 Hz, 1H), 6.13 J= 7.1 Hz, 1H), 7.41 1H), 7.48 2H), 7.74 1H), 7.83 3H).
3 C-nmr (CDCI 3 8 18.4, 18.82, 18.85, 27.6, 43.7, 48.2, 71.4, 125.9, 126.3, 127.2, 127.6. 127.7, 128.2, 128.7, 132.0, 132.5, 133.5, 170.3, 172.8.
C,
9
H
23
NO
3 (MW 313.40, Mass Spectroscopy (MH' 314)).
Example Synthesis of N-(4-phenylbutanoyl)-L-alanine iso-butyl ester Following General Procedure BB and using 4-phenylbutanoic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel and purification was by extraction with EtO followed by washes with aqueous K,C0 3 and aqueous HC1.
NMR data was as follows: 'H-nmr (CDC1,): 6 0.92 J= 6.7 Hz, 6H), 1.38 J= 7.1 Hz, 3H), 1.96 3H), 2.21 J 7.1 Hz, 2H), 2.64 J= 7.3 Hz, 2H), 3.90 2H), 4.59 (quint., J 7.2 Hz, 1H), 6.31 IH), 7.16 3H), 7.24 2H).
WO 98/28268 PCT/US97/2296 660 3 C-nmr (CDCI 3 5 18.3, 18.75, 18.78, 26.8, 27.5, 34.9, 35.3, 47.8, 71.2, 125.7, 128.2, 128.3, 141.3, 172.1, 173.0.
C,
7 H,2NO 3 (MW 291.39, Mass Spectroscopy (MH' 292)).
Example B 11 Synthesis of N-(5-phenylpentanoyl)-L-alanine iso-butyl ester Following General Procedure BB and using 5-phenylpentanoic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as an oil. The reaction was monitored by tic on silica gel and purification was by extraction with Et,O followed by washes with aqueous KCO 3 and aqueous HC1.
NMR data was as follows: 'H-nmr (CDC1,): S 7.23 2H), 7.17 3H), 6.30 1H), 4.59 (quint., J 7.3 Hz, 1H), 3.91 2H), 2.61 J 7.2 Hz, 2H), 2.22 J 7.2 Hz, 2H), 1.93 1H), 1.66 4H), 1.38 J= 7.2 Hz, 3H), 0.92 J 6.7 Hz, 6H).
3 C-nmr (CDC1 3 8 173.1, 172.3, 142.0, 128.2, 128.1, 125.6, 71.2, 47.8, 36.1, 35.5, 30.8, 27.5, 25.0, 18.80, 18.77, 18.4.
C,gH, 7
NO
3 (MW 305.39, Mass Spectroscopy (MH' 306)).
Example B12 Synthesis of N-[(4-pyridyl)acetyl]-D,L-alanine iso-butyl ester Following General Procedure BF and using 4-pyridylacetic acid hydrochloride (Aldrich) and (DL)-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 64 0 -66 0 C. The reaction was monitored by tic on silica gel (Rf 0.43 10% methanol/dichloromethane) and purification was by silica gel chromatography.
NMR data was as follows: WO 98/28268 PCTUS97/22986 661 'H-nmr (CDCI,): 8 8.51 (dd, J 1.6, 2.8, 1.6, 2H); 7.23 (dd, J= 4.3, 1.6, 4.4, 2H); 6.71 J= 6.8, 1H); 4.56 (quint., J= 7.3, 7.2, 1H); 3.88 2H); 3.53 2H); 1.89 1H); 1.36 J= 7.2, 3H); 0.88 J= 6.7, 6H).
"C-nmr (CDCI 3 8 173.5, 169.3, 150.5, 144.4, 125.1, 72.1, 48.9, 43.0, 28.2, 19.5, 19.5, 18.9.
C,,
4 H2oN0 3 (MW 264, Mass Spectroscopy (MH' 265)) Example B13 Synthesis of N-(phenylacetyl)-L-alanine iso-butyl ester Following General Procedure BB and using phenylacetyl chloride (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 45 0 -47 0 C. The reaction was monitored by tic on silica gel and purification was by extraction with Et,O followed by washes with aqueous KCO 3 and aqueous HC1.
NMR data was as follows: 'H-nmr (CDCI,): 8 7.24-7.39 5H), 6.14 1H), 4.58 J= 7.3 Hz, 1H), 3.88 2H), 3.58 2H), 1.90 1H), 1.35 J= 7.2 Hz, 3H), 0.89 J 6.7 Hz, 6H).
3 C-nmr (CDCl 3 8 172.8, 170.4, 134.5, 129.3, 128.9, 127.2, 71.3, 48.1, 43.5, 27.5, 18.9, 18.8, 18.4.
C
15 H,iNO 3 (MW 263.34, Mass Spectroscopy (MH' 264)).
Example B14 Synthesis of 2 3 4 -dichlorophenyl)acetamido]butyric acid iso-butyl ester Following General Procedure BI above and using 3,4-dichlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above) the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure.
NMR data was as follows: WO 98/28268 PCT/US97/22986 662 'H-nmr (CDCI,): 6 7.36 3H), 6.03 (bd, 1H), 4.54 1H), 3.87 (m, 2H), 3.49 2H), 1.93 2H), 1.72 1H), 0.88 6H), 0.80 3H).
Example Synthesis of 2 -[(3-methoxyphenyl)acetamido]butyric acid iso-butyl ester Following General Procedure BI above and using 3-methoxyphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared frollowing General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure.
NMR data was as follows: 'H-nmr (CDCI,): 6 6.75 4H), 5.93 (bd, 1H), 4.51 1H), 3.83 (m, 2H), 3.75 2H), 3.52 2H), 1.82 2H), 1.60 1H), 0.84 6H), 0.74 3H).
C
1 7
H,
5
NO
4 (MW 307.39, Mass Spectroscopy (MH' 309)).
Example B16 Synthesis of 2 -[(4-nitrophenyl)acetamido]butyric acid iso-butyl ester Following General Procedure BI above and using 4-nitrophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure.
NMR data was as follows: 'H-nmr (CDCI,): 8 8.16 2H), 7.44 2H), 6.04 (bd, 1H), 4.55 (m, 1H), 3.86 2H), 3.66 2H), 1.86 2H), 1.67 1H), 0.85 6H), 0.81 3H).
C
16 H,,N'Os (MW 322.36, Mass Spectroscopy (MH' 323)).
Example B17 Synthesis of 2 3 4 -methylenedioxyphenyl)acetamido]butyric acid iso-butyl ester WO 98/28268 PCT/US97/22986 663 Following General Procedure BI above and using 3 ,4-(methylenedioxy)phenyl acetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure.
NMR data was as follows: 'H-nmr (CDCI,): 8 6.72 3H), 5.92 (bd, 1H), 4.54 1H), 3.86 (m, 2H), 3:66 2H), 1.86 2H), 1.66 1H), 0.89 6H), 0.79 3H).
Example B 18 Synthesis of 2-[(thien-3-yl)acetamido]butyric acid iso-butyl ester Following General Procedure BI above and using 3-thiopheneacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure.
NMR data was as follows: 'H-nmr (CDCI,): 8 7.37 1H), 7.16 1H), 7.04 1H), 6.05 (bd, 1H), 4.57 1H), 3.66 2H), 1.93 2H), 1.67 1H), 0.91 6H), 0.86 3H).
Example B19 Synthesis of 2-[(4-chlorophenyl)acetamido]butyric acid iso-butyl ester Following General Procedure BI above and using 4-chlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure.
NMR data was as follows: WO 98/28268 PCT/US97/22986 664 'H-nmr (CDCI,): 8 7.22 2H), 7.11 2H), 5.80 1H), 4.44 (m, 1H), 3.78 2H), 3.43 2H), 1.77 2H), 1.56 1H), 0.83 6H) 0.71 3H).
Example Synthesis of 2-[(3-nitrophenyl)acetamidolbutyric acid iso-butyl ester Following General Procedure BI above and using 3-nitrophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure.
NMR data was as follows: 'H-nmr (CDC13): 8 8.15 2H), 7.65 1H), 6.08 1H), 4.46 (m, 1H), 3.92 2H), 3.68 2H), 1.91 2H), 1.75 1H), 0.98 6H) 0.71 3H).
Example B21 Synthesis of 2-[(2-hydroxyphenyl)acetamido]butyric acid iso-butyl ester Following General Procedure BI above and using 2-hydroxyphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure.
NMR data was as follows: 'H-nmr (CDCI,): 8 7.14 1H), 7.01 1H), 6.93 1H), 6.79 (m, 1H), 6.46 1H), 4.51 1H), 3.87 2H), 3.57 2H), 2.01 2H), 1.75 1H), 0.89 6H), 0.85 3H).
Example B22 Synthesis of 2-[(2-naphthyl)acetamido]butyric acid iso-butyl ester WO 98/28268 PCT/US97/22986 665 Following General Procedure BI above and using 2-naphthylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure.
NMR data was as follows: 'H-nmr (CDC1,): 6 7.83 7H), 5.95 1H), 4.58 1H), 3.84 (m, 2H), 3.75 2H), 1.89 2H), 1.63 1H), 0.91 6H), 0.81 3H).
C2 0
H,
5
NO
3 (MW 327.42, Mass Spectroscopy (MH' 328)).
Example B23 Synthesis of 2-[(2,4-dichlorophenyl)acetamido]butyric acid iso-butyl ester Following General Procedure BI above and using 2,4-dichlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure.
NMR data was as follows: 'H-nmr (CDCI 3 6 7.49 1H), 7.22 2H) 5.98 1H), 4.52 (m, 1H), 3.86 2H), 3.61 2H), 1.84 2H), 1.62 1H) 0.87 6H), 0.80 3H).
Example B24 Synthesis of 2-[(4-bromophenyl)acetamido]butyric acid iso-butyl ester Following General Procedure BI above and using 4-bromophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure.
NMR data was as follows: WO 98/28268 PCT/US97/22986 666-- 'H-nmr (CDCI,): 6 7.43 2H), 7.19 2H) 5.85 1H), 4.51 1H), 3.81 2H), 3.47 2H), 1.84 2H), 1.61 1H) 0.84 6H), 0.76 (t, 3H).
C,,H,2NO 3 Br (MW 356.26, Mass Spectroscopy (MH' 358)).
Example Synthesis of 2-I(3-chlorophenyl)acetamido])butyric acid iso-butyl ester Following General Procedure BI above and using 3-chlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure.
NMR data was as follows: 'H-nmr (CDCI,): 5 7.25 3H), 7.12 1H) 5.80 1H), 4.52 (m, 1H), 3.86 2H), 3.50 2H), 1.87 2H), 1.67 1H) 0.88 6H), 0.77 3H).
C,,H,,NO
3 C1 (MW 311.81 Mass Spectroscopy (MH' 313)).
Example B26 Synthesis of 2-[(3-fluorophenyl)acetamido]butyric acid iso-butyl ester Following General Procedure BI above and using 3-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure.
NMR data was as follows: 'H-nmr (CDCI,): 8 7.31 1H), 7.01 3H) 5.95 1H), 4.54 (m, 1H), 3.84 2H), 3.54 2H), 1.88 2H), 1.65 1H) 0.87 6H), 0.81 3H).
CJ
6 H,zNO 3 F (MW 295.35 Mass Spectroscopy (MH' 296)).
WO 98/28268 PCT/US97/22986 667 Example B27 Synthesis of 2 -I(benzothiazol-4-yl)acetamido]butyric acid iso-butyl ester Following General Procedure BI above and using 4-benzothiazol-4-yl acetic acid (Chemservice) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure.
NMR data was as follows: 'H-nmr (CDCI,): 6 7.82 1H), 7.51-7.21 4H) 5.84 1H), 4.51 1H), 3.90 2H), 3.79 2H), 1.78 2H), 1.58 1H) 0.80 6H), 0.66 3H).
Example B28 Synthesis of 2-[(2-methylphenyl)acetamido]butyric acid iso-butyl ester Following General Procedure BI above and using 2-methylphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure.
NMR data was as follows: 'H-nmr (CDCI,): 8 7.18 4H), 5.79 1H), 4.54 1H), 3.85 (m, 2H), 3.59 2H), 3.29 3H), 1.81 2H), 1.59 1H) 0.87 6H), 0.77 3H).
C,
7 HsNO 3 (MW 291.39 Mass Spectroscopy 291)).
Example B29 Synthesis of 2-[(2-fluorophenyl)acetamido]butyric acid iso-butyl ester Following General Procedure BI above and using 2-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic WO 98/28268 PCT/US97/22986 668 on silica gel and purification was by filtration as described in the general procedure.
NMR data was as follows: 'H-nmr (CDCI,): 5 7.28 1H), 7.09 3H) 6.03 1H), 4.54 (m, 1H), 3.87 2H), 3.57 2H), 1.89 2H), 1.64 1H) 0.88 6H), 0.80 3H).
Example Synthesis of 2-[(4-fluorophenyl)acetamido] butyric acid iso-butyl ester Following General Procedure BI above and using 4-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure.
NMR data was as follows: 'H-nmr (CDC1,): 6 7.20 2H), 6.97 2H) 5.87 1H), 4.492 (m, 1H), 3.83 2H), 3.48 2H), 1.86 2H), 1.60 1H) 0.87 6H), 0.78 3H).
C,
6
H,,NO
3 F (MW 295.35 Mass Spectroscopy (MH- 296)).
Example B31 Synthesis of 2 -[(3-bromophenyl)acetamido]butyric acid iso-butyl ester Following General Procedure BI above and using 3-bromophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure.
NMR data was as follows: 'H-nmr (CDCI,): 6 7.45 2H), 7.23 2H) 5.95 1H), 4.55 (m, 1H) 3.84 2H) 3.55 2H), 1.89 2H), 1.68 1H) 0.91 6H), 0.81 3H).
WO 98/28268 PCT/US97/22986 669
C,,
6 H2NO 3 Br (MW 356.26 Mass Spectroscopy 357)).
Example B32 Synthesis of 2-[(3-trifluoromethylphenyl)acetamido butyric acid iso-butyl ester Following General Procedure BI above and using 3-trifluoromethylphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure.
NMR data was as follows: 'H-nmr (CDC13): 6 7.52 1H), 7.47 2H) 6.01 1H), 4.56 (m, 1H), 3.86 2H), 3.61 2H), 1.84 2H), 1.62 1H) 0.87 6H), 0.80 3H).
C,
1
H,
2
NO
3
F
3 (MW 345.36 Mass Spectroscopy (MH' 345)).
Example B33 Synthesis of 2-I(2-thienyl)acetamido]butyric acid iso-butyl ester Following General Procedure BI above and using 2-thiopheneacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure.
NMR data was as follows: 'H-nmr (CDC1,): 6 6.89 3H), 6.07 (bd, 1H), 4.50 1H), 3.82 (m, 2H), 3.71 2H), 1.85 2H), 1.62 1H), 0.81 6H), 0.75 3H).
CIH,,NO
3 S (MW 283.39, Mass Spectroscopy (MH 284)).
Example B34 Synthesis of 2-(phenylacetamido)butyric acid iso-butyl ester Following General Procedure BH above and using phenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure WO 98/28268 PCT/US97/22986 670 BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by chromatography on silica gel using 9:1 toluene:EtOAc as the eluant.
NMR data was as follows: 'H-nmr (CDCI,): 8 7.17-7.28 5H), 6.23 (bd, 1H), 4.51 1H), 3.86 2H), 3.54 2H), 1.87 2H), 1.62 1H), 0.87 6H), 0.78 3H).
C,
6
H
23
NO
3 (MW 277.36, Mass Spectroscopy (MH' 277)).
Example Synthesis of N-(phenylacetyl)valine 2-methylbutyl ester Step A. Preparation of N-(phenylacetyl) valine To a stirred solution of 5.15 g (44 mmol) of valine (Bachem) in 50 mL (100 mmol) of 2N NaOH cooled to 0°C was added dropwise 5.3 mL (40 mmol) of phenylacetyl chloride (Aldrich). A colorless oil precipitated. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours, washed with 50 mL diethyl ether, acidified to pH 2-3 with aqueous HC1. The white precipitate formed was filtered off, washed thoroughly with water, followed by diethyl ether to give 7.1 g (30 mmol, 69% yield) of the title compound.
NMR data was as follows: 'H-nmr (DMSO-d 6 6 12.63 1H), 8.25 J= 8.6 Hz, 1H), 7.27 (m, 4.15 1H), 3.56 J= 13.8 Hz, 1H), 3.47 J= 13.8 Hz, 1H), 2.05 1H), 0.87 J 6.8, Hz, 3H), 0.84 J 6.8 Hz, 3) 3 C-nmr (DMSO-d 6 8 173.2, 170.4, 136.6, 129.0, 128.2, 126.3, 57.1, 41.9, 30.0, 19.2, 18.0
C,
3
H,
7
NO
3 (MW=235.29; Mass Spectroscopy (MH' 236)) Step B. Synthesis of N-(phenylacetyl)valine 2-methylbutyl ester Following General Procedure BC and using the N-(phenylacetyl) valine prepared in Step A above and 2-methylbutan-l-ol (Aldrich), the title compound WO 9828268 PCT/US97/22986 671 was prepared as a diastereomeric mixture. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure.
NMR data was as follows: 'H-nmr (CDCI,): 8 7.25-7.40 5H), 5.95 1H), 4.56 1H), 3.84- 4.00 2H), 3.61 2H), 2.10 1H), 1.68 1H), 1.38 1H), 1.15 (m 1H), 0.82-0.94 9H), 0.76 3H).
"C-nmr (CDCl 3 5 171.84, 171.81, 170.7, 134.6, 129.31, 129.27, 128.9, 127.3, 69.8, 57.0, 43.7, 33.9, 31.3, 25.9, 25.8,, 18.9, 17.4, 16.34, 16.27, 11.12, 11.07.
C,,H,
7 N0 3 (MW 305.42, Mass Spectroscopy (MH 306)).
Example B36 Synthesis of N-(phenylacetyl)-L-methionine iso-butyl ester L-Methionine (0.129g, 0.869 mmols) (Aldrich) was taken-up in dioxane mL) and treated with a saturated solution of sodium bicarbonate (5.0 mL) followed by phenylacetyl chloride (Aldrich) (0.114 mL, 0.822 mmols). After stirring for 17 hours at room temperature the mixture was diluted with ethyl acetate, the layers separated and the aqueous layer acidified to pH 2 with HC1. The crude product was extracted into ethyl acetate, dried over sodium sulfate, vacuum dried and used without further purification.
N-phenylacetyl-L-methionine (0.1285 g, 0.447 mmol) was dissolved in mL dioxane and iso-butyl alcohol (0.2 mL) and treated with EDC (0.094 g, 0.492 mmol), and catalytic DMAP (0.015g). After stirring for 17 hours at 23 0 C, the mixture was evaporated at reduced pressure to an oil, the residue was diluted in EtOAc and washed with 0.1 N HCI and saturated sodium bicarbonate.
Chromatography on silica gel using 98:2 CHCI 3 /MeOH as eluant provided the pure product.
NMR data was as follows: 'H-nmr (CDCl 3 8 7.4-7.23 5H), 6.14 (bd, 1H), 4.70 1H), 3.89 2H), 3.62 2H), 2.43 2H), 2.12 1H), 1.93 2H), 0.94 6H).
C
17
H,
5
NO
3 S (MW 323.17, Mass Spectroscopy 323) WO 98/28268 PCT/US97/22986 672 Example B37 Synthesis of N-(phenylacetyl)-L-leucine iso-butyl ester L-Leucine (Aldrich) (0.114g, 0.869 mmols) was taken-up in dioxane mL) and treated with a saturated solution of sodium bicarbonate (5.0 mL) followed by phenylacetyl chloride (Aldrich) (0.114 mL, 0.822 mmols). After stirring for 17 hours at room temperature the mixture was diluted with ethyl acetate, the layers separated and the aqueous layer acidified to pH 2 with HCI. The crude product was extracted into ethyl acetate, dried over sodium sulfate, vacuum dried and used without further purification.
N-Phenylacetyl-L-leucine (0.0081 g, 0.038 mmol) was dissolved in 2.0 mL CHC13 (EtOH free) and iso-butyl alcohol (0.055 mL) and treated with P-EPC (100 mg, 0.87 milliequivalents). The mixture was rotated for 4 days, filtered through a plug of cotton and the filtrate evaporated at reduced pressure to an oil which was sufficiently pure for testing.
NMR data was as follows: 'H-nmr (CDClI): 8 7.22 5H), 5.57 1H), 4.35 1H), 3.35 (m, 3H), 1.35 4H), 0.68 9H).
C,
1
H,
7
NO
3 (MW 305.40, Mass Spectroscopy 305)).
Example B38 Synthesis of N-[(3-chlorophenyl)acetyljalanine 3-methylbut-2-enyl ester Following General Procedure BC above and using N-(3-chlorophenylacetyl alanine (from Example BD above) and 3-methylbut-2-en-l-ol (Aldrich), the title compound can be prepared. The reaction was monitored by tic on silica gel and purification was by liquid chromatography using 30% EtOAc/hexane as the eluant.
NMR data was as follows: 'H-nmr (CDCI 3 6 7.39-7.16 4H), 6.06 (bd, 1H), 5.38-5.29 1H), 4.63 J= 9Hz, 2H), 3.56 2H), 1.79 3H), 1.7 3H), 1.39 J= 9Hz, 3H).
WO 98/28268 PCT/US97/22986 673 Example B39 Synthesis of N-[(3-chlorophenyl)acetyl]alanine cyclopropylmethyl ester Following General Procedure BC above, and using N-(3-chlorophenylacetyl alanine (from Example BD above) and cyclopropylmethanol (Aldrich), the title compound can be prepared. The reaction was monitored by tic on silica gel and purification was by liquid chromatography using 3:7 EtOAc:hexane as the eluant.
NMR data was as follows: 'H-nmr (CDCI,): 6 7.2-7.1 4H), 6.09 (bs, 1H), 4.6 (dq, J= 9 Hz, 1H), 3.96 (dd, J= 9Hz, 2H), 3.59 2H), 1.2 J= 9Hz, 3H), 1.2-1.0 (m, 1H), 0.603-0.503 2H), 0.300-0.203 2H).
Example Synthesis of N-((3-chlorophenyl)acetyl]alanine 2-thienylmethyl ester Following General Procedure BC above, and using N-(3-chlorophenylacetyl alanine (from Example BD above) and 2-thiophenemethanol (Aldrich) the title compound can be prepared. The reaction was monitored by tic on silica gel and purification was by liquid chromatography using 3:7 EtOAc:hexane as the eluant.
NMR data was as follows: 'H-nmr (CDCI,): 6 7.37-6.97 7H), 5.97 J= 14 Hz, 2H), 4.6 (dq, J 9 Hz, 1H), 3.76 2H), 1.38 J= 9Hz, 3H).
Example B41 Synthesis of N-[(3-chlorophenyl)acetyl]alanine (1-methylcyclopropyl)methyl ester Following General Procedure BC above, and using N-(3-chlorophenylacetyl alanine (from Example BD above) and (1-methylcyclopropyl)methanol (Aldrich) the title compound can be prepared. The reaction was monitored by tic on silica gel and purification was by liquid chromatography using 3:7 EtOAc:hexane as the eluant.
NMR data was as follows: WO 98/28268 PCTIUS97/22986 674 'H-nmr (CDCI,): 6 8.6 (bd. J =9 Hz. I 3.86 J =14 Hz, 2H), 3.4 2H), 2.29 J 9 Hz, lH), 1.3 J 9Hz, 3H), 1.03 3H), 0.5-0.4 (in, 2H), 0.4-0.28 (in, 2H).
Example B42 Synthesis of N- I(3-chlorophenyl)acetyli alanine 3-thienylmethyl ester Following General Procedure BC above, and using N-(3-chlorophenylacetyl alanine (from Example 3D above) and 3-thiopheneinethanol (Aldrich) the title compound can be prepared. The reaction was monitored by tic on silica gel and -purification was by liquid chromatography using 3:7 EtOAc:hexane as the eluant.
NMR data was as follows: 'H-rnr (CDCI,): 5 8.03 (bd, J 9 Hz, I 7.56-7.5 (in, I1H), 7.47 (bs, 7.4-7.17 (mn, 4H), 7.06 J1 9 Hz, 5.1 2H), 4.3 (dq, 111), 1.3 (d, J=9 Hz, 3H).
Example B43 Synthesis of N-I(3-chlorophenyl)acetyll alanine 2-methylcyclopentyl ester Following General Procedure BC above, and using N-(3)-chlorophenylacetyl alanine (from Example BD above) and 2-inethylcyclopentanol (Aldrich) the title compound can be prepared. The reaction was monitored by tic on silica gel and purification was by liquid chromatography using 3:7 EtOAc:hexane as the eluant.
NMR data was as follows: 'H-nmr (CDCI,): 8 7.39-7.16 (in, 4H1), 6.3 (bd, 1H), 4.79-4.7 (mn, IH), 4.6-4.25 (mn, J 9 Hz, 1H), 3.577 2H1), 2.09-1.8 (in, 2H), 1.74-1.6 (mn, 2H1), 1.39 (dd, J1=9 Hz, 1.2 (dt, J 9 Hz, I 0.979 (dd, J 9 Hz. 211)
C
17
H,,NO
3 CI (MW 323.82, Mass Spectroscopy (MW- 323).
Example 344 Synthesis of NY-1(3-chlorophenvl)acetylj alanine 2-methylprop-2-enyl ester WO 98/28268 PCTIUS97/22986 675 Following General Procedure BC above, and using N-(3-chlorophenylacetyl alanine (from Example BD above) and 2 -methylprop-2-en-1-ol (Aldrich) the title compound can be prepared. The reaction was monitored by tic on silica gel and purification was by liquid chromatography using 3:7 EtOAc:hexane as the eluant.
NMR data was as follows: 'H-nmr (CDCI,): 8 7.39-7.16 4H), 6.03 (bs, 1H), 4.77 2H), 4.7- 4.29 3H), 2.59 2H), 1.73 3H), 1.43 J= 9 Hz, 3H) C,sH,NO0 3 C1 (MW 295.76, Mass Spectroscopy (MH' 295)).
Example Synthesis of N-[(3-chlorophenyl)acetyl]alanine cyclohex-2-enyl ester Following General Procedure BC above, and using N-(3-chlorophenylacetyl alanine (from Example BD above) and cyclohex-2-en-l-ol (Aldrich) the title compound can be prepared. The reaction was monitored by tic on silica gel and purification was by liquid chromatography using 3:7 EtOAc:hexane as the eluant.
NMR data was as follows: 'H-nmr (CDCI,): 6 8.6 (bd, J= 9 Hz, 1H), 7.4-7.2 4H), 6.0-5.8 (m, 1H), 5.7-5.5 1H), 5.1 (bs, 1H), 4.13-4.29 1H), 3.5 2H), 2.1-1.9 (m, 2H), 1.8-1.69 1H), 1.69-1.49 4H), 1.3 (dd, J= 9 Hz, 3H)
C,
7 H2 0
NO
3 CI (MW 321.8, Mass Spectroscopy (MHW 321.2)).
Example B46 Synthesis of 2 -phenylbenzoxazol-5-yl)acetyl]alanine iso-butyl ester Following General Procedure BI above, and using 5-(2-phenylbenzoxazol)yl-acetic acid (CAS# 62143-69-5) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared.
NMR data was as follows: WO 98/28268 PCT/US97/22986 676 'H-nmr (CDCI,): 8 8.24 3H), 7.68 1H), 7.51 5H), 6.04 (m, 1H), 4.58 1H), 3.85 2H), 3.68 2H), 1.9 1H), 1.35 3H), 0.87 6H).
C,,H,
4 N,0 4 (MW 380, Mass Spectroscopy (MH' 381)).
Example B47 Synthesis of N-[(3-methylthiophenyl)acetyl]alanine iso-butyl ester Following General Procedure BI above, and using 3-methylthiophenylacetic acid (CAS# 18698-73-2) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure.
NMR data was as follows: 'H-nmr (CDCI,): 6 7.14 2H), 7.01 1H), 4.56 1H), 3.88 (m, 2H), 3.54 2H), 2.46 3H), 1.89 1H), 1.35 3H) 0.85 6H).
C,
6
H,
3
NO
3 S (MW 309, Mass Spectroscopy (MH' 310)).
Example B48 Synthesis of N-4-[(2-furyl)acetyl]alanine iso-butyl ester Following General Procedure BI above, and using 2-furylacetic acid (CAS# 2745-26-8) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure.
NMR data was as follows: 'H-nmr (CDCI,): 6 7.36 1H), 6.34 1H), 6.21 1H), 4.56 (m, 1H), 3.91 2H), 3.61 2H), 1.92 1H), 1.38 3H) 0.89 6H).
C,
3
H,,NO
4 (MW 253, Mass Spectroscopy (MH' 254)).
Example B49 Synthesis of N-[(benzofuran-2-yl)acetyl]alanine iso-butyl ester WO 98/28268 PCT/US97/22986 677 Following General Procedure BI above, and using benzofuran-2-ylacetic acid (Maybridge) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure.
NMR data was as follows: 'H-nmr (CDCI,): 6 7.51 1H), 7.44 1H),7.25 2H), 6.67 (s, 1H), 4:60 1H), 3.87 2H), 3.77 2H), 1.88 IH), 1.38 3H), 0.87 6H).
C
1
,H,INO
4 (MW 303, Mass Spectroscopy (MH' 304)).
Example Synthesis of N-[(benzothiophen-3-yl)acetyllalanine iso-butyl ester Following General Procedure BI above, and using thianaphthen-3-ylacetic acid (Lancaster) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure.
NMR data was as follows: 'H-nmr (CDCI,): 8 7.89 1H), 7.76 1H), 7.38 3H), 6.07 (m, 1H), 4.57 1H), 3.92 2H), 3.82 4H), 1.84 1H), 1.32 3H) 0.85 6H).
C,
7
H,,NO
3 S (MW 319, Mass Spectroscopy (MH' 320)).
Example B51 Synthesis of N-[(2-chloro-5-thienyl)acetyl]alanine iso-butyl ester Following General Procedure BI above, and using 5-chloro-2-thienyl)acetic acid (CAS# 13669-19-7) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure.
WO 98/28268 PCTIUS97/22986 678 NMR data was as follows: 'H-rnr (CDCl 3 86 6.77 (in, IR), 6.68 1H), 6.31 (bin, 1H), 4.59 (in, IH)j 3.91 (in, 2H), 3.38 2H), 1.90 (in, IH), 1.39 3H) 0.89 6H).
C
13 HjINO 3 SCI (MW 303, Mass Spectroscopy (MH' 303)).
Example B52 Synthesis of N-I( 3 -methylisoxazol-5-yI)acetyljalanine iso-butyI ester Following General Procedure BI above, and using yl)acetic acid (CAS# 19668-85-0) and alanine iso-butyl ester (prepared -following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
NMR data was as follows: 'H-nmr (CDCl 3 86 6.07 2H), 4.56 (in, IH), 3.92 (in, 2H), 3.68 (s, 2H), 2.29 3H), 1.94 (in, 1H), 1.89 '31H) 0.91 6H).
C
13
H.,
0 N,0 4 (MW 268, Mass Spectroscopy (MH' 269)).
Example B53 Synthesis of 2 -phenylthiothienyl)acetyljalanine iso-butyl ester Following General Procedure BI above, and using (2-phenylthiothienyl)acetic acid and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
NMR data was as follows: 'H-nmr (CDCI,): 8 7.21-7.11 (in, 6H), 6.92 lH), 4.56(mn, lH), 3.87 (mn, 211), 3.72 2H), 1.94 (in, lH), 1.38 3H) 0.89 6H).
C
19
H,'
3
NO
3 Sl (MW 377, Mass Spectroscopy (MW' 378)).
Example B54 Synthesis of N- (6-methoxybenzothiophen-2-yl)acetyll alanine iso-butyl ester WO 98/28268 PCT/US97/22986 679 Following General Procedure BI above, and using (6-methoxythianaphthen- 2-yl)acetic acid and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure.
NMR data was as follows: 'H-nmr (CDCI,): 5 7.59 1H), 7.33 1H), 7.16 1H), 7.03 (dd, 1H), 4:56 1H), 3.87(s, 3H), 3.84 2H), 3.76 2H),l.85 1H), 1.30 3H) 0.86 6H).
CiH, 3
NO
4 S (MW 349, Mass Spectroscopy (MH' 350)).
Example Synthesis of N-[(3-phenyl-1,2,4-thiadiazol-5-yl)acetylalanine iso-butyl ester Following General Procedure BI above, and using (3-phenyl-1,2,4thiadiazol-5-yl)acetic acid (CAS# 90771-06-5) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure.
NMR data was as follows: 'H-nmr (CDCI,): 8 7.47 5H), 4.66 1H), 4.16 2H), 3.91 (m, 2H), 1.93 1H), 1.48 3H) 0.93 6H).
C
17
H,,N
3 0 3 S (MW 347, Mass Spectroscopy (MH' 348)).
Example B56 Synthesis of N-I2-phenyloxazol-4-yl)acetyl]alanine iso-butyl ester Following General Procedure BI above, and using (2-phenyloxazol-4yl)acetic acid (CAS# 22086-89-1) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure.
WO 98/28268 PCT/US97/22986 680 Example B57 Synthesis of 3 -methylphenyl)acetyl]alanine iso-butyl ester Following General Procedure BI above, and using 3 -methylphenylacetic acid (Aldrich) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure.
NMR data was as follows: 'H-nmr (CDCI,): 8 7.21 1H), 7.07 3H), 4.54 1H), 3.83 (m, 3.52 2H), 2.35 3H), 1.87 1H), 1.32 3H), 0.88 6H).
C
16 H3NO 3 (MW 277, Mass Spectroscopy (MH 278)).
Example B58 Synthesis of 2 5 -difluorophenyl)acetyl]alanine iso-butyl ester Following General Procedure BI above, and using 2 acid (Aldrich) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure.
NMR data was as follows: 'H-nmr (CDCI,): 8 7.08-6.94 3H), 4.57 1H), 3.91 2H), 3.56 2H), 1.92 1H), 1.41 3H) 0.91 6H).
C,
5 HNO0 3
F
2 (MW 299, Mass Spectroscopy (MH' 300)).
Example B59 Synthesis of N-( 3 ,5-diflurophenyl)acetyl]alanine iso-butyl ester Following General Procedure BI above, and using acid (Aldrich) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure.
WO 98/28268 PCT/US97/22986 681 NMR data was as follows: 'H-nmr (CDCI,): 6 6.81 2H), 6.74 1H), 6.06 1H), 4.57 (m, 1H), 3.92 2H), 3.51 2H), 1.94 1H), 1.36 3H) 0.87 6H).
C
15
H
19
NO
3 F, (MW 299, Mass Spectroscopy (MH' 300)).
Example Synthesis of N-[(3-thienyl)acetyl]alanine iso-butyl ester Following General Procedure BI above, and using 3-thiopheneacetic acid (Aldrich) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure.
NMR data was as follows: 'H-nmr (CDC1,): 6 7.33 1H), 7.14 1H), 7.01 1H), 6.09 (m, 1H), 4.58 1H), 3.88 2H), 3.60 2H), 1.91 1H), 1.37 3H) 0.92 6H).
Optical Rotation: [oC]23 -52 (c 1 MeOH) 589 nm.
C
13
H
19 NO0S (MW 269, Mass Spectroscopy (MH' 269)).
Example B61 Synthesis of 4 -methylphenyl)acetyl]-L-alanine iso-butyl ester Following General Procedure BI above, and using 4-methylphenylacetic acid (Aldrich) and L-alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure.
NMR data was as follows: 'H-nmr (CDCl,): 8 7.11 4H), 5.93 1H), 4.58 1H), 3.88 (m, 2H), 3.54 2H), 2.33 3H), 1.89 1H), 1.32 3H), 0.89 6H).
C
1
,H,
3
NO
3 (MW 277.35, Mass Spectroscopy (MH' 278)).
WO 98/28268 PCT/US97/22986 682 Example B62 Synthesis of N-(phenylacetyl)-L-alanine S-l-(methoxycarbonyl) iso-butyl ester Following General Procedure BK and using (S)-(+)-2-hydroxy-2methylbutyric acid (Aldrich) in place of the amino acid, methyl hydroxy-2-methylbutyrate was prepared.
Methyl (S)-(+)-2-hydroxy-2-methylbutyrate was then coupled with carbobenzyloxy-L-alanine (Aldrich) using General Procedure BE to provide carbobenzyloxy-L-alanine S-l-(methoxycarbonyl) iso-butyl ester.
Carbobenzyloxy-L-alanine S-l-(methoxycarbonyl) iso-butyl ester (1.0 g) was then dissolved in 20 mL of methanol and 6N HCI (0.5 mL) and palladium on carbon (0.1 g) were added. This reaction mixture was hydrogenated at 40 psi of hydrogen on a Parr apparatus for 5 hours at room temperature and then filtered through a pad of Celite. The filtrate was concentrated at reduced pressure to provide L-alanine S-1-(methoxycarbonyl) iso-butyl ester hydrochloride (98% yield).
L-Alanine S-l-(methoxycarbonyl) iso-butyl ester hydrochloride was then coupled to phenylacetic acid using General Procedure BG to provide the title compound.
NMR data was as follows: 'H-nmr (CDCI,): 6 7.35 7.20 5H), 6.22 (bd, 1H), 4.83 1H), 4.65 1H), 3.68 3H), 3.55 2H), 2.21 1H), 1.40 3H), 0.97 3H), 0.93 3H).
"1C-nmr (CDC1 3 8 173.25, 171.18, 170.22, 135.11, 129.94, 129.50, 127.88, 52.67, 48.49, 43.98, 30.53, 19.21, 18.75, 17.58.
Example B63 Synthesis of N-[(3-nitrophenyl)acetyl]-L-alanine iso-butyl ester Following General Procedure BH above and using 3-nitrophenylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by recrystallization from butyl chloride.
WO 98/28268 PCT/US97/22986 683 NMR data was as follows: 'H-nmr (CDCI,): 6 8.17 2H), 7.68 1H), 7.52 IH), 6.18 (m, 1H), 4.48 1H), 3.94 2H), 3.67 2H), 1.93 1H), 1.42 3H), 0.91 3H).
Optical Rotation: 3 -49 (c 5, MeOH).
Example B64 Synthesis of N-[(3,5-difluorophenyl)acetyl]alanine ethyl ester Following General Procedure BG and using 3,5-difluorophenylacetic acid (Aldrich) and alanine ethyl ester (Aldrich), the title compound was prepared as a solid with a melting point of 93°-95 0 C. The reaction was monitored by tic on silica gel (Rf 0.8 in EtOAC) and purification was by chromatography on silica gel using EtOAc as the eluant followed by recrystallization from 1-chlorobutane.
NMR data was as follows: 'H-nmr (DMSO-d 6 6 1.30 3H); 3.52 2H).
C,
3
H,
5
NO
3 F, (MW 271.26, Mass Spectroscopy (MH- 271)).
Example Synthesis of N-[(3-nitrophenyl)acetyl]methionine ethyl ester Following General Procedure BG above and using 3-nitrophenylacetic acid (Aldrich) and methionine ethyl ester hydrochloride (Aldrich), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by recrystallization from butyl chloride.
NMR data was as follows: 'H-nmr (CDCI,): 6 8.18 1H), 8.15 1H) 7.66 1H), 7.48 1H), 6.30 1H), 4.67 1H), 4.21 2H), 3.67 2H), 2.47 2H), 2.12 2 2.08 3H), 1.27 3H).
Optical Rotation: 3 -30 (c 5, MeOH).
Example B66 Synthesis of N-[(3-chlorophenyl)acetyl]alanine iso-butyl ester WO 98/28268 PCT/US97/22986 684 Following General Procedure BG above and using 3-chlorophenylacetic acid (Aldrich) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel.
NMR data was as follows: 'H-nmr (CDCI,): 6 7.29 3H), 7.18 1H), 6.0 1H), 4.56 (m, 1H), 3.89 2H), 3.53 2H), 1.91 1H), 1.39 3 0.91 3H).
Optical Rotation: [aC] 2 3 -45 (c 5, MeOH).
C,
1 H,NO0 3 Cl (MW 297.78, Mass Spectroscopy (MH' 297)).
Example B67 Synthesis of N-[(3-chlorophenyl)acetyljalanine 2-(N,N-dimethylamino)ethyl ester Following General Procedure BC above, and using N-(3-chlorophenylacetyl)alanine (from Example BD above) and 2-(N,N-dimethyl amino) ethanol (Aldrich), the title compound can be prepared. The reaction was monitored by tic on silica gel and purification was by liquid chromatography using 0.1:2:0.79
NH
4 OH:EtOH:CHCl 3 as the eluant.
NMR data was as follows: 'H-nmr (CDCI,): 7.37 1H), 7.33-7.2 3H), 4.675-4.6 1H), 4.37 1H), 4.25-4.13 1H), 3.6 J 7 Hz, 2H), 2.86 (bs, 2H), 2.3 (s, 6H), 1.23 J= 9 Hz, 3H).
CI
5
H,
1
N,O
3 C1 (MW 313.799, Mass Spectroscopy 313)).
Example B68 Synthesis of 2-[(3,5-dichlorophenyl)acetamido]hexanoic acid methyl ester Following General Procedure BF above, an using acid (from Example BC above) and L-norleucine methyl ester hydrochloride (Bachem), the title compound was prepared as a solid having a melting point of 77 0 -78 0 C. The reaction was monitored by tic on silica gel (Rf 0.70 in EtOAC/hexanes) and purification was by flash chromatography on silica gel using 40% EtOAc/hexanes as the eluant.
WO 98/28268 PCTIUS97/22986 685 NMR data was as follows: 'H-nmr (CDCI,): 6 7.20 7.18 6.6 4.55 3.7 3.5 3.4 2.0 1.8 1.6 1.2 0.8 3 C-nmr (CDCI 3 6 173.54, 169.67, 138.43, 135.72, 128.33, 128.07, 78.04, 77.62, 77.19, 53.04, 52.90, 43.14, 32.57, 27.87, 22.81, 14.41.
Example B69 Synthesis of N-[(3,5-diclorophenyl)acetyl]-L-alanine iso-butyl ester Following General Procedure BF above, and using acid (from Example BC above) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 115°-116 C. The reaction was monitored by tic on silica gel (Rf 0.40 in 3% methanol/dichloromethane) and purification was by flash chromatography on silica gel using 3% methanol/dichloromethane as the eluant.
NMR data was as follows: 'H-nmr (CDC1,): 6 7.27 J= 2 Hz, 1H), 7.19 2H), 6.22 J= 6 Hz, 1H), 4.59 (quint., J= 7 Hz, 1H), 3.9 J= 4 Hz, 2H), 3.5 2H), 1.9 (m, 1H), 1.4 J= 7 Hz, 3H), 0.91 J= 7 Hz, 6H).
"1C-nmr (CDCI 3 8 173.45, 169.37, 138.31, 135.75, 128.39, 128.11, 78.04, 77.61, 77.19, 72.19, 54.03, 48.97, 43.12, 28.24, 19.52, 19.49, 19.09.
CsHlgNO 3 C1, (MW 331.9, Mass Spectroscopy (MH 332)).
Example Synthesis of N-(cyclohexylacetyl)-L-alanine iso-butyl ester Following General Procedure BB above, and using cyclohexylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 92 0
C-
93°C. The reaction was monitored by tic on silica gel (Rf 0.39 in 1:3 EtOAc:hexane) and purification was by extraction with EtO followed by washes with aqueous KCO 3 and aqueous HC1.
NMR data was as follows: WO 98/28268 PCT/US97/22986 686 'H-nmr (CDCI,): 5 0.93 J= 6.7 Hz. 6H), 0.85-1.01 2H), 1.05-1.35 3H), 1.40 J= 7.1 Hz, 3H), 1.60-1.85 6H), 1.95 1H), 2.06 J 7.0 Hz, 2H), 3.92 2H), 4.61 1H), 6.08 (bd, 1H).
3 C-nmr (CDC1 3 8 18.7, 18.9, 26.0, 26.1, 27.6, 33.0, 35.3, 44.6, 47.9, 71.4, 171.8, 173.3.
C,sH, 7
NO
3 (MW 269.39, Mass Spectroscopy (MH' 270)).
Example B71 Synthesis of N-(cyclopentylacetyl)-L-alanine iso-butyl ester Following General Procedure BB above, and using cyclopentylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 62 0
C-
64 0 C. The reaction was monitored by tic on silica gel (Rf 0.37 in 1:3 EtOAc:hexane) and purification was by extraction with EtzO followed by washes with aqueous KCO 3 and aqueous HC1.
NMR data was as follows: 'H-nmr (CDC1,): 5 0.87 J= 6.8 Hz, 6H), 1.01-1.17 2H), 1.34 (d, J= 7.2 Hz, 3H), 1.40-1.62 4H), 1.70-1.83 2H), 1.89 1H), 2.15 (m, 3H), 3.86 2H), 4.55 1H), 6.30 J= 7.1 Hz, 1H).
13C-nmr (CDCl 3 8 18.4, 18.78, 18.80, 24.8 (very high), 27.5, 32.27, 32.32, 36.9, 42.5, 47.7, 71.2, 172.2, 173.2.
Elemental Analysis-Calc C, 65.85; H, 9.87; N, 5.49; Found C, 66.01; H, 10.08; N, 5.49.
C,
4
H,
5 NO, (MW 255.36, Mass Spectroscopy (MH' 256)).
Example B72 Synthesis of N-[(cyclohex-l-enyl)acetyl]-L-alanine iso-butyl ester Following General Procedure BB above, and using cyclohex-l-enyl acetic acid (Alfa) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 49 0 C-51 0 C. The reaction was monitored by tic on silica gel (Rf 0.40 in 1:3 WO 98/28268 PCT1US97/22986 687 EtOAc:hexane) and purification was by extraction with EtO followed by washes with aqueous KCO and aqueous HCI.
NMR data was as follows: 'H-nmr (CDCl,): 8 0.91 J 4.5 Hz, 3H), 0.93 J 6.7 Hz. 3H), 1.40 J= 7.2 Hz, 3H), 1.52-1.70 4H), 1.97 3H), 2.06 (bs, 2H), 2.89 2H), 3.92 2H), 4.59 1H), 5.65 1H), 6.33 J= 6.6 Hz, 1H).
1 3 C-nmr (CDCl 3 8 18.7, 18.91, 18.93, 21.9, 22.7, 25.3, 27.6, 28.3, 46.1, 47.9, 71.4, 127.1, 132.5, 170.6, 173.1.
Elemental Analysis-Calc C, 67.38; H, 9.42; N, 5.24; Found C, 67.34; H, 9.54; N, 5.16.
C,,H,sNO 3 (MW 267.37, Mass Spectroscopy (MH' 268)).
Example B73 Synthesis of N-[(3-chlorophenyl)acetyl]alanine 3-methylbut-2-enyl thioester Following General Procedure BC above, and using chlorophenyl)acetyl] alanine and 3-methyl-2-butene thioester (TCI), the title compound can be prepared. The reaction was monitored by tic on silica gel and purification was by liquid chromatography using 3:7 EtOAc:Hexane as the eluant.
NMR data was as follows: 'H-nmr (DMSO-d 6 6 5.2-5.075 1H), 4.37 (dq, J 9 Hz, 1H), 3.56 3.43 J= 12 Hz, 2H), 1.266 J= 12 Hz, 6H) 1.3 J= 9 Hz, 3H).
C,
6
H,
0 NO,CIS (MW 325.86, Mass Spectroscopy 325)).
Example B74 Synthesis of N-[(2-phenyl)-2-fluoroacetyl]alanine ethyl ester Following General Procedure BF above, and using a-fluorophenyl acetic acid (Aldrich) and alanine ethyl ester (Aldrich), the title compound was prepared. The reaction was monitored by tic on silica gel (Rf 0.75 in 1:1 EtOAc:hexane) and purification was by chromatography on silica gel using 1:2 ethyl acetate/hexanes as the eluent.
WO 98/28268 PCT/US97/22986 688 NMR data was as follows: 'H-nmr (DMSO-d): 6 1.14 3H), 1.34 3H), 4.07 2H), 4.33 (m, 1H), 5.84 1H), 6.01 1H), 7.40-7.55 5H), 8.87 1H).
C,
3
H,
6
NO
3 F (MW 253.27, Mass Spectroscopy (MH' 253)).
Example Synthesis of N-( 3 ,5-difluorophenylacetyl)-L-phenylglycine methyl ester Following General Procedure BF above, and using acid (Aldrich) and L-phenylglycine methyl ester hydrochloride (Bachem), the title compound was prepared.
NMR data was as follows: 'H-nmr (CDC13): 6 =7.4-7.3 5H), 6.9-6.7 3H), 6.55 (d 1H, 7.1 Hz), 5.56 (d 1H 7 Hz), 3.72 (s 3H), 3.57 (s 2H) 13C-nmr (CDCl 3 8 197.6, 177.6, 171.8, 169.3, 136.7, 129.6, 129.3, 127.8, 113.0, 112.9, 112.7, 111.4, 103.8, 103.5, 65.1, 57.2, 53.5, 45.1, 43.3, 43.3
C,
17
HNO
3
F
2 (MW 319.31, Mass Spectroscopy (MH +320)).
Example B76 Synthesis of N-(3,5-difluorophenylacetyl)-L-phenylglycine iso-butyl ester The 3,5-difluorophenylacetic acid (Aldrich) was EDC coupled to Lphenylglycine methyl ester hydrochloride (Bachem) via General Procedure BF above.
The resulting compound was placed in a large excess of the desired alcohol.
A catalytic amount of dry NaH was added, and the reaction was followed by tic until the presence of starting material was no longer detected. The reaction was quenched with a few milliliters of IN HC1, and after a few minutes of stirring saturated aqueous NaHCO, was added. The volume of the reaction mixture was reduced on a rotary evaporator until the excess alcohol was removed and then the remaining residue was taken up in ethyl acetate and additional water was added. The organic phase was washed with saturated aqueous NaCI and dried WO 98/28268 PCTUS97/22986 689 over MgSO.. The solution was stripped free of solvent on a rotary evaporator, and the crude product residue was then further purified by chromatography.
NMR data was as follows: 'H-nmr (CDCl 3 8 7.35-7.3 (m 5H), 6.8-6.7 (m 3H) 6.60 (d 1H, 7 Hz), 5.55 (d 1H 7.1 Hz), 3.9 (m 2H), 3.60 (s 2H), 1.85 (m 1H 7 Hz), 0.8 (q 6H 7 Hz) 3 C-nmr (CDC1 3 6 171.3, 169.3, 165.4, 138.5, 137.0, 129.5, 129.2, 127.6, 113.1, 113.0, 112.8, 112.7, 103.8, 103.5, 103.2, 75.5, 57.2, 43.4, 43.3, 28.2, 19.3 C2oH,,NO 3
F
2 (MW 361.39, Mass Spectroscopy (MH +362)).
Example B77 Synthesis of N-(cyclopentylacetyl)-L-phenylglycine methyl ester Following General Procedure BD above, and using cyclopentylacetic acid (Aldrich) with L-phenylglycine methyl ester hydrochloride (Bachem) the title compound was prepared.
NMR data was as follows: 'H-nmr (CDC1 3 6 7.35 5H), 6.44 (bd, 1H), 5.6 1H), 3.72 3H), 2.24 (bs, 3H), 1.9-1.4 6H), 1.2-1.05 2H) 3 C-nmr (CDC1 3 6 172.3, 171.7, 136.7, 129.0, 128.6, 127.3, 56.2, 52.7, 42.5, 36.9, 32.40, 32.38, 24.8 Example B78 Synthesis of N-(cyclopentylacetyl)-L-alanine methyl ester Following General Procedure BD above, and using cyclopentylacetic acid (Aldrich) with L-alanine methyl ester hydrochloride (Sigma) the title compound was prepared.
NMR data was as follows: 'H-nmr (CDCI 3 6 6.38 1H), 4.50 1H), 3.65 3H), 2.13 (bs, 3H), 1.80-1.00 (m (includes d at 1.30, 3H), 11H) WO 98/28268 PCT/US97122986 690 "C-nmr (CDC 3 6 173.7, 172.5, 52.1, 47.6, 42.3, 36.8, 32.15, 32.14, 18.0
C,,H,,NO
3 (MW 213.28, Mass Spectroscopy (MH' 214)).
Example B79 Synthesis of N-(cyclopropylacetyl)-L-phenylglycine methyl ester Following General Procedure BD above, and using cyclopropylacetic acid (Aldrich) with L-phenylglycine methyl ester hydrochloride (Bachem), the title compound was prepared.
NMR data was as follows: 'H-nmr (CDCl 3 6 7.35 5H) 6.97 (bd, J= 7.2 Hz, 1H) 5.59 (d, J= 7.8 Hz, 1H), 3.71 3H), 2.17 2H), 1.05-0.95 1H), 0.62 2H), 0.02 2H) 3 C-nmr (CDC1 3 6 171.9, 174.6, 136.6, 129.0, 128.5, 127.2, 56.1, 52.7, 41.0, 6.9, 4.37, 4.33 Example Synthesis of N-(cyclopropylacetyl)-L-alanine methyl ester Following General Procedure BD above, and using cyclopropylacetic acid (Aldrich) with L-alanine methyl ester hydrochloride (Sigma), the title compound was prepared.
NMR data was as follows: 'H-nmr (CDCI 3 6 6.60 1H), 4.55 1H), 3.69 3H), 2.10 (m, 2H), 1.34 3H), 0.95 1H), 0.58 2H) 0.15 2H) 13C-nmr (CDC13): 6 173.7, 172.3, 52.3, 47.7, 41.0, 18.2, 6.7, 4.27, 4.22 Example B81 Synthesis of N-[(3-nitrophenyl)acetyll-L-methionine iso-butyl ester Following General Procedure BH above, and using nitrophenylacetic acid (Aldrich) and L-methionine (Aldrich), the title compound was prepared as a tan oil. The reaction was monitored by tic on silica gel.
WO 98/28268 PCT/US97/22986 691 NMR data was as follows: 'H-nmr (CDCI 3 8 8.16 (m,2H) 7.67 (d,lH) 7.32 1H), 6.31 (bd, 1H), 4.69 1H), 3.90 2H), 3.68 2H), 2.47 2H), 2.15 1H), 2.02 (s, 3H), 1.90 2H), 0.91 6H).
C
17
H,-
4 NOS (MW 368.4, Mass Spectroscopy (MH' 368)).
Additionally, each of the carboxylic acids described above (or the carboxylic acids prepared by hydrolysis of the above carboxylic acid esters) could be coupled with an appropriate a-aminolactam to provide for compounds of the formula: R2 R1 -I--NH
O
m where R'-[Z]-NH-CHR2-C(O)- is the residue of the carboxylic acid R 2 Z, and m are as defined above) and W" is selected from the following structures: WO 98/28268 WO 9828268PCTIUS97/22986 N
-N
0 r N R H 0 H
N
R=H.EtX=S02.
R=H
R=HEzX=O, R=1 0
N"\
N
H 0
H
WO 98/28268 PCTIUS97/22986 I re ~r~ o
C
t2Ow K0- 17
A
1 0
K
~HO a-o 4
H
o 0 0 WO 98/28268 PCTIUS9722986 694-- I ~a Po13 iI 0 0'2o \Ls
I
~-(ir 0 Ya 6 \Y3h 0
K
1 Ij
I
I
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I
0K
I
WO 98/28268 PCT/US97/22986 695 a a (\NflK
NV
r
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O4
I
0 '4 Q-\Nr-
C-
1 WO 98/28268 :9 -696- PCT[US97/22986 p 0 I g 0 J .4 2 .4 0 I 2 2
I,,
a p ~i7) pr~
I
4- 2 0 I- m 0
I-
p 2 4- 2 0 1~~o 0 (-p 2 0 .1 0 0 0 0 ->9 2 >9 0 02 WO 98/28268 WO 9828268PCTIUS97/22986 697 X--O.s x--o.S
X--O.S
x~o~sX--O.S Zo 0 so 0 0 0 sK 0 QQ0 0~ 0Q Nil0 ~Ci N NNil N H N Ni i nH OH i
NI
N NHN NI NHO H NA5N y~N NcAH O-kNH NANHONHNIA 0 Z o HO003 Q 1
S
N~ 8 A~V~ Nil n~NAnHnI HNlnNlN Nil NI 00
DI
o h 0Ni 0'N NA0VN 0o NilN IINi NAQ N yN Qv Ni i H N i N N- H4 HQ N, H N N FN N FN N INN N FINN 1- o.~NHN NHN N "OH Ne OUe MeO Ot-Bu-O NMe2
M
I I I I I3~ I I HIN N IN N FIN N HN N HN N I-N N HNNN N FN N IN N -IN N0 HIN N HN N F-IN I-I.N N N NI> HN N FIN N IN N HN N HN N HN Q b oD 0 0 0 0 0 0 0o \a o I~I I II I I HN N IN N HN NHN NHN N HN N N HN N I-IN N O 0 0 S0 0NHN 0 EI0 NtN QS2 0 I~ ~HN [IIN IVN FIN N ()oI N F IN NII ~1 N N N N HNN I-IN N INN N F HN N FIN N [N N 0 a 0 o 0 0 0 NNI 0 o 0 N C2 S 00 I 1~ rr I i rr~l r N II
I
IN I INN N N S0 FIN N H N N FIN N N 0 0 S O O I iO o r o -O, o
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0 IIN 0 N N -IN N 0 N N I- N N N N NHN N FIN N N N IN NHFN N 0 0 o 0 i0I _NW 2 0OMe MeOl 0I-Btit-O 0 FIN 0 N FIN NN HN N 5 N N I-IN Nj NN N N 5
I-IN~
5 N FN N III I L I I I I I FIN NN N N I-IN N N N N N [IN N l N IIN NHFN N HIN NHFN N 0 oa 0 o\ 0 0 0 0 o o o 0 [IN N IN N N IN N HN N N IN N HIN N F N [iNj N IN N HN J N N FIN N HN N FIN N I-I N)a -o o o oZoo 0 0 00 -O N E 02 v x I I Pt 0
C
C
N
Ch
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Go 0 o Ol\ 0 N NII N NI-I NHNII N 0 N N NIl N NH NZi] N N i l NI 1 I I
I
0 13N 0 S N X i 0N 00 ~NH NH ~INH ZNHl Nlf NINH O~H N NH HN NH NHNI- N NH N Ni -sN- NH N.N- i NH 1 N Ni l NH N NH N Ni l N Ni N N Nil N Ni N Ni II0 0 1 QNo NHN NI N N- i i N NH N 1 i I I i Nil N HNi NHN N NHN N NON:ilNrHNNH N- N NH 0
N
'I I I I I e S ~g 0 o-In]-o 'MNon so~ PQ0 0EI 0vo11 N N N H N NN N H N NH N N INH N
NHNH
sQ, Q 0Q s Oo OQQ oQ i)oJ 0 N N 0 OQ 0 NH NHN NHN NH N NH
NNH
Zo pla or s OSQ 13NQ 1 3 NQ0 s 0 01: o 1r NH NH N H N NH N 00%/A l I N NH N NHN NHN NHN NH os O 0 lo 3 OSIINNH N NH 0N3Q 0 0 $Q OQ OuI1 0 L1041a 0 N NHN NI] NNH NNH NNH NH NH N NHN NH S1 I I I I I I N I- N H N NH N NH N NH N NH N NH N NH NH NH NH Qo o o o o oA oQ 0 0 0 o HO0 N NH N NH N NHN NHN NH N N NH NHN NHN NHN NHN NH 0 01113-10 08 O Vfr 0 o'aVYN HO yo o 0 f 0 0 o o o N NH/ 'N NI-I N N NI NIl -Jn NjH/N N N H N yNH N NH- N Nil 0 I I I II r cc~'S' rC\0 0 0 O aK' 0 0 0NH NH N NH N NH N NH- N NHN N H NH N NH N NN H N N -A0 r IPNH S O 13N NHNNH N NHo:Z o0 (4 0 0 0-K '0\o 2 0 H N NH N HNN N1 NH NHN NQ ,N NyH NH N NH N NH QO3 0oKN34 oSKI j~s~ Q lt~ 1IJ 1 NH NH N NH-IN NH N P NH N NH N NH N PNN NH NN N I I
I
OIQ Qq QQ Qo 00QQO0Z N NNNH N NH N NHO N NH N NH N NHN NH N NHN NH N NH Qo00 0o 0o 0 0 Q 0oQ 0 0 0 ~H 0 N NH N NH N NH N NH N NH N NN NH4 N NH N NH N NH N NH N NH GoI:P I pI pI I I1 IpIpI
I
cc0 0-Ing-i0 oorv gyy 'ENH o o~J 00 NA NoN.4II- ,11 N!k(o S" Nl -L:NII-4y IN H NJ4yNH N-kNH NK NlN i 0 Kr~I N I H N I II.NIkI (I s~0 L7o 0 0 0 0 RNo4 0 00 rt 0 NHN NN N N N l N N NH~ 0 NH 1 N NH N NH N NH NAI NH
N
N NH N N
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QQ 400 O0e\o 01 0 0 N H HN N N NH N NH N NH N N HN N N NN NH N NH NNH N NHN NN N HN NH Q0 oN 0 Q Qo1~ QoQ 0 0 0 0
H
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Q
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Q
NH IHN NH ~j~NH~ 5 5 NO~. NHY a-yl 0 o o am-In- i 0ONO, T 0 T 0 yN NN yN yNH
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0 1 I0 IN ?o Os Q 0 N1QO3 SQOQ O Q O Q O17-j QN NNH N Q 0Q NH NH0 NH Nk NH N NH NI NH N NH N NHI N NH N NH N- i NHN NI N N Hl 0 1 1 1/-1I I
I
00 0 N ~o ~o of~ Q~/N NH0%k0H
NHI
NH N~H( NH NH N0 H N H NH N H N NH ~0 N OHO H NJK I NH N N u uP 0 i S KGo NH NHN 7 0 NH N NH" 91T Q NH N 4 H 'N NH '4 NO 0 0 0 NNNO O N1Ir-J NH H V, II&1 a- M t' I IN -NI IN N FIN 0 0 I IN NI? FIN N I IN Q VN NI-IN QIIN N 09 0 0 0 0 N 0IN IIN I N 0 FIN N IN N N N IIN N 0 7- 0 0 0~ S N, 0 NTS I 4 N FIQN II N N N I IN IN o 0 0 0 02 NJ
N
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jIf I 11 14 1 Iti I N -4 ItJ -N IIJ I N I -N 1 1ff 41 IN 1 -N FIN
OH:::
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N
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0 Nil ti- Nil I p
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0 r00 Nil 1 14 tl I tVk 14 0 0 00 0 0 00 N NI]I N Nil N Nil I p I pI q 0 i1 IN NI Nil N NJil 1l' 0 Nil I'l- tlill Nil uN- Nil I 2 I N- Nil N~ N NNil J NNil Qo Q0 N' 0 Nil N Nil 14 N N N Nil I pI pIpI N Nf'l N Nil11 N Il I p >0 I FIN N I I I FIN NUIN N IN N I I I I N I N -N FIN No N= lIN= 0 ~N 0 0 ,Nb N0 N N I iFI I N I I IN N IIN N I N 0 0 1IN N 0,1 US0 0 II I I
I
IfN rN IN N INj N HI N _IN\ 0 V)0 o 0 0=N 0 0 0N TS N 0 N.
thN IN N IFIN I I N1IJi 1FIN CN IIN N I N I IIN N FIN N IN N N N 0 I I IN rN FIN N 02 02 NN N 0 FINJ N FIN Nf IN N F IN N FIN N FIN -N F-IN N FIN N FIN N FIN N FIN N FIN rs r .o S. NI I Pit IPit I-I N -N IIN
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N
N 0 0 Sx Ifl 1 1l~ I P~f PIJ Il ll IliIN r) 1PIN IPIN N 11N_ 14 t 1-I l I P 02or tjIJI(.) I-) NilN N~ IINI 0r<1 I IN -Ni I
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N
e N e, N 0 NH Nil N t 0 Nil 0 0 0I NJ N N Nl N Nil o I N -N 0~ o N 0 IIN N 0 0 0~ 0 PIN N P IN N IN N liN N IuN N IN N (_QjN N _j
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C) 0 IIN -N I PIN r N 0 0 PIN N 0o Io-) 0
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-N
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)0 O 0 0- N 0 0 0N TS N>0 NV IIN II I I N0 I ~NIIN0 l 0 00 0 Cs N
N
pI N IN( NoPIN N 0 jN 0o0 N N N~\ I I 111 N UIN N 0 0N 00 00
II!!
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N
I N i d N I-N N IIN N IUN N I-IN N, IN N o o)70 ~)70 o)-N 0 0 0 0 N<0 N, 0 N, -IN N I 0 cs
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0 I I N -d N N 'N
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N N 1
N
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N
N N =N f=N N N S r 1111 N N I IN N NN I-IN N)N IIN N )tj, J! 0 0 0 1 0 hPI
N
o 04 N 0S) N 0 N S v -1 j=N r N r N r N FN I) r hNZI INXZ2> IN N IAIN IIJ N [IN N I-IN N 0 o 0N)N N,S 0 0 NZl N1
NN
0 S K
N=
-N 1 =N N=NN N Sr S I I I S S s N N PIN -N PIN N 0N N N N 0d\ n N N
N
S S I N rNN N f--N IN N 0 1 0S O( j OO N) N Jo N N 0 o N/s N_-o NY FM N r-=N r-N
SI
I It/J 0
J
(Wk/N~ \iJ C1 N N~ Nil Ni ~0 N--1 U N N-/ ~0 0 0 N- VI~, II N~P I N
II
ox 0 0~ N N c 0 x N NN Nil 0 0 No- N O'z N
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ININ N IIN -N N Il N IIN N IIN N r O N N t o N -2 ooi WO 98/28268 PCT/US97/22986 735 Example Bio-1 Cellular Screen for the Detection of Inhibitors of B-Amyloid Production Numerous compounds of formula I above were assayed for their ability to inhibit P-amyloid production in a cell line possessing the Swedish mutation.
This screening assay employed cells (K293 human kidney cell line) which were stably transfected with the gene for amyloid precursor protein 751 (APP751) containing the double mutation Lys 65 1 Met 6 52 to Asn 65 1 Leu 6 (APP751 numbering) in the manner described in International Patent Application Publication No. 94/105698 and Citron et al.
1 2 This mutation is commonly called the Swedish mutation and the cells, designated as "293 751 SWE", were plated in Coring 96-well plates at 2-4 x 10 4 cells per well in Dulbecco's minimal essential media (Sigma, St. Louis, MO) plus 10% fetal bovine serum. Cell number is important in order to achieve p-amyloid ELISA results within the linear range of the assay to 2.5 ng per mL).
Following overnight incubation at 37 0 C in an incubator equilibrated with carbon dioxide, media were removed and replaced with 200 IL of a compound of formula I (drug) containing media per well for a two hour pretreatment period and cells were incubated as above. Drug stocks were prepared in 100% dimethyl sulfoxide such that at the final drug concentration used in the treatment, the concentration of dimethyl sulfoxide did not exceed and, in fact, usually equaled 0.1%.
At the end of the pretreatment period, the media were again removed and replaced with fresh drug containing media as above and cells were incubated for an additional two hours. After treatment, plates were centrifuged in a Beckman GPR at 1200 rpm for five minutes at room temperature to pellet cellular debris from the conditioned media. From each well, 100 of conditioned media or appropriate dilutions thereof were transferred into an ELISA plate precoated with antibody 266 Seubert, Nature (1992) 359:325-327] against amino acids 13-28 of p-amyloid peptide as described in International Patent Application WO 98/28268 PCT/US97/22986 736 Publication No. 94/10569 and stored at 4 0 C overnight. An ELISA assay employing labelled antibody 3D6 Seubert, Nature (1992) 359:325-327] against amino acids 1-5 of P-amyloid peptide was run the next day to measure the amount of P-amyloid peptide produced.
Cytotoxic effects of the compounds were measured by a modification of the method of Hansen, et al.' 3 To the cells remaining in the tissue culture plate was added 25 pL of a 3 4 ,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) (Sigma, St. Louis, MO) stock solution (5 mg/mL) to a final concentration of 1 mg/mL. Cells were incubated at 37 0 C for one hour, and cellular activity was stopped by the addition of an equal volume of MTT lysis buffer (20% w/v sodium dodecylsulfate in 50% dimethylformamide, pH 4.7).
Complete extraction was achieved by overnight shaking at room temperature.
The difference in the OD 562 nm and the OD 6 5 0 nm was measured in a Molecular Device's UVm, microplate reader as an indicator of the cellular viability.
The results of the P-amyloid peptide ELISA were fit to a standard curve and expressed as ng/mL P-amyloid peptide. In order to normalize for cytotoxicity, these results were divided by the MTT results and expressed as a percentage of the results from a drug free control. All results are the mean and standard deviation of at least six replicate assays.
The test compounds were assayed for P-amyloid peptide production inhibition activity in cells using this assay. The results of this assay demonstrate that the compounds of formula I inhibit P-amyloid peptide production by at least as compared to control.
Example Bio-2 In Vivo Suppression of -Amyloid Release and/or Synthesis This example illustrates how the compounds of this invention could be tested for in vivo suppression of P-amyloid release and/or synthesis. For these WO 98/28268 PCT/US97/22986 737 experiments, 3 to 4 month old PDAPP mice are used [Games et al., (1995) Nature 373:523-527]. Depending upon which compound is being tested, the compound is usually formulated at between I and 10 mg/mL. Because of the low solubility factors of the compounds, they may be formulated with various vehicles, such as corn oil (Safeway, South San Francisco, CA); 10% ethanol in corn oil; 2 -hydroxypropyl-p-cyclodextrin (Research Biochemicals International, Natick MA); and carboxy-methyl-cellulose (Sigma Chemical Co., St. Louis
MO).
The mice are dosed subcutaneously with a 26 gauge needle and 3 hours later the animals are euthanized via CO, narcosis and blood is taken by cardiac puncture using a 1 cc 25G 5/8" tuberculin syringe/needle coated with solution of M EDTA, pH 8.0. The blood is placed in a Becton-Dickinson vacutainer tube containing EDTA and spun down for 15 minutes at 1500 xg at 5°C. The brains of the mice are then removed and the cortex and hippocampus are dissected out and placed on ice.
1. Brain Assay To prepare hippocampal and cortical tissue for enzyme-linked immunosorbent assays (ELISAs) each brain region is homogenized in volumes of ice cold guanidine buffer (5.0 M guanidine-HCl, 50 mM Tris-HC1, pH 8.0) using a Kontes motorized pestle (Fisher, Pittsburgh PA). The homogenates are gently rocked on a rotating platform for three to four hours at room temperature and stored at -20 0 C prior to quantitation of P-amyloid.
The brain homogenates are diluted 1:10 with ice-cold casein buffer [0.25% casein, phosphate buffered saline (PBS), 0.05% sodium azide, 20 pg/ml aprotinin, 5 mM EDTA, pH 8.0, 10 tg/ml leupeptin], thereby reducing the final concentration of guanidine to 0.5 M, before centrifugation at 16,000 xg for minutes at 4°C. Samples are further diluted, if necessary, to achieve an optimal range for the ELISA measurements by the addition of casein buffer with 0.5 M WO 98/28268 PCT/US97/22986 738 guanidine hydrochloride added. The P-amyloid standards (1-40 or 1-42 amino acids) were prepared such that the final composition equaled 0.5 M guanidine in the presence of 0.1% bovine serum albumin (BSA).
The total P-amyloid sandwich ELISA, quantitating both p-amyloid (aa 1-40) and p-amyloid (aa 1-42) consists of two monoclonal antibodies (mAb) to Pamyloid. The capture antibody, 266 Seubert, Nature (1992) 359:325-327], is specific to amino acids 13 28 of P-amyloid. The antibody 3D6 [Johnson- Wood et al., PNAS USA (1997) 94:1550-1555], which is specific to amino acids 1 5 of P-amyloid, is biotinylated and served as the reporter antibody in the assay. The 3D6 biotinylation procedure employs the manufacturer's (Pierce, Rockford IL) protocol for NHS-biotin labeling of immunoglobulins except that 100 mM sodium bicarbonate, pH 8.5 buffer is used. The 3D6 antibody does not recognize secreted amyloid precursor protein (APP) or full-length APP but detects only P-amyloid species with an amino terminal aspartic acid. The assay has a lower limit of sensitivity of -50 pg/ml (11 pM) and shows no crossreactivity to the endogenous murine P-amyloid peptide at concentrations up to 1 ng/ml.
The configuration of the sandwich ELISA quantitating the level of Pamyloid (aa 1-42) employs the mAb 21F12 [Johnson-Wood et al., PNAS USA (1997) 94:1550-1555] (which recognizes amino acids 33-42 of p-amyloid) as the capture antibody. Biotinylated 3D6 is also the reporter antibody in this assay which has a lower limit of sensitivity of -125 pg/ml (28 pM).
The 266 and 21F12 capture mAbs are coated at 10 gg/ml into 96 well immunoassay plates (Costar, Cambidge MA) overnight at room temperature.
The plates are then aspirated and blocked with 0.25% human serum albumin in PBS buffer for at least 1 hour at room temperature, then stored desiccated at 4°C until use. The plates are rehydrated with wash buffer (Tris-buffered saline, 0.05% Tween 20) prior to use. The samples and standards are added to the WO 98/28268 PCT/US97/22986 739 plates and incubated overnight at 4 0 C. The plates are washed 3 times with wash buffer between each step of the assay. The biotinylated 3D6, diluted to p.g/ml in casein incubation buffer (0.25% casein, PBS, 0.05% Tween 20, pH 7.4) is incubated in the well for 1 hour at room temperature. Avidin-HRP (Vector, Burlingame CA) diluted 1:4000 in casein incubation buffer is added to the wells for 1 hour at room temperature. The colorimetric substrate, Slow TMB-ELISA (Pierce, Cambridge MA), is added and allowed to react for minutes, after which the enzymatic reaction is stopped with addition of 2 N
HSO
4 Reaction product is quantified using a Molecular Devices Vmax (Molecular Devices, Menlo Park CA) measuring the difference in absorbance at 450 nm and 650 nm.
2. Blood Assay The EDTA plasma is diluted 1:1 in specimen diluent (0.2 gm/1 sodium phosphate.H,O (monobasic), 2.16 gm/1 sodium phosphate.7H,O (dibasic), 0.5gm/1 thimerosal, 8.5 gm/1 sodium chloride, 0.5 ml Triton X-405, 6.0 g/l globulin-free bovine serum albumin; and water). The samples and standards in specimen diluent are assayed using the total P-amyloid assay (266 capture/3D6 reporter) described above for the brain assay except the specimen diluent was used instead of the casein diluents described.
Formulations other than those described above can also be used for oral delivery and intravenous delivery to a mammal. For oral delivery, the compound can be mixed with either 100% corn oil or, alternatively, in a solution comtaining 80% corn oil, 19.5% oleic acid and 0.5% labrafil. The compound can be mixed with the above solutions in concentrations ranging from 1 mg/mL to 10 mg/mL. The compound in solution is preferably administered orally to the mammal at a dose volume of 5 mL/kg of body weight. For IV delivery, the compound is preferably mixed with a solution of 3% ethanol, 3% solutol HS-15 and 94% saline. The compound is preferably mixed with the above solution in concentrations ranging from 0.25 mg/mL to 5 mg/mL. The 740 compound in solution is preferably administered by IV to the mammal at a dose volume of 2 mL/kg of body weight.
From the foregoing description, various modifications and changes in the composition and method will occur to those skilled in the art. All such modifications coming within the scope of the appended claims are intended to be included therein.
The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and S"comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
*oe*

Claims (20)

1. A method for inhibiting P-amyloid peptide release and/or its synthesis in a cell which method comprises administering to such a cell an amount of a compound or a mixture of compounds effective in inhibiting the cellular release and/or synthesis of 1-amyloid peptide wherein said compounds are represented by formula I: R NH C C(H), C wherein R' is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic; W, together with forms a cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl, or substituted cycloalkenyl group wherein each of said cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl or substituted cycloalkenyl group is optionally fused to form a bi- or multi-fused ring system (preferably no more than 5 fused rings) with one or more ring structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group which, in turn, each of such ring structures are optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkoxy, thioalkoxy, Ssubstituted thioalkoxy, nitro, cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, N- 742 alkylamino, N,N-dialkylamino, N-substituted alkylamnino, N-alkyl N-substiiured alkylarno, N ,N-disubstituted alkylamino, -NHC(O)R 4 -NI-SO,R 4, -C(O)NH 2 -C(O)NHR 4 -C(O)NR 4 R 4 -S(O)R 4 -S(O) 2 R 4 -S(O) 2 NHR 4 and. -S(O) 2 NR 4RI where each R 4 is independently selected from the group consisting of alkyl, substituted alkyl, or aryl; X is selected from the group consisting of oxo thiooxo hydroxyl thiol and hydro Y is represented by the formula: wherein each R' is independently selected from the group consisting iof alkyl,- substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynvi, cycloalkyl, aryl, heteroaryl and heterocyclic; .Z is represented by the formula where T is selected from the group consisting of a bond covalently linking R' to oxygen, :sulfur, -NR5 where R 5 is hydrogen, acyl, alkyl, aryl or heteroaryl group; X' is hydrogen, hydroxy or fluoro, XV is hydrogen, hydroxy or fluoro, or X' and XV together form in oxo group; with the proviso that when T is oxygen, sulfur or NR 5 then X' and XV are each hydrogen; 742A m isi1; n is an integer equal to 0, 1 or 2; p is an integer equal to 0 or 1 such that when p is zero, the ring defined by W and is unsaturated at the carbon atom of ring attachment to Y 743 and when p is one, the ring is saturated at the carbon atom of ring attachment to Y, with the following provisos: A. when R' is 3 ,5-difluorophenyl, R 2 is -CH-I, Z is -CH 2 n is 1, and p is 1, then W, together with CH and C=X, does not form a 2- (S)-indanol group; B. when R' is phenyl, R' is -CH3, Z is n is 1, and p is 1, then W, together with CH and C=X, does not form a trans-2-hydroxy- cyclohex- 1-yl group; 1. C. when R' is phenyl, Z is n is 0, and p is 1, then W, together with CH and C does not form a gamnmabuyrolactone group or a 5,-iehlgnuauyoatn group; D. when R' -is phenyl, Z is n is0, andp is 1,thenW, together with >CH and does not form a e-caprolactam group; E. when R' is cyclopropyl, R 2 is -CH 3 Z is n is 1. and p is 1, then W, together with CH and C=X, does not form an N- :metnylcaprolactam group; F. when RI is 4 -chlorobenzoyi-CH,-. R 2 is -CH 3 Z is -CH- 2 n is 1, and p is 1, then W, together with CH and C does not form an 2, 3-dihydro-l1-methyl-5-pheny.. i- 1 4 -benzodiazepin2one. G. whnR s 2 -phenylphenyl, R2i C3 s-CH 2 is 1, and p is 1, then W, together with CH and C does not form an 7- 7 -dihydro-6H-dibenz[b,d]azepin-6one; H when R' is CH 3 OC(O)CH,. R2 is -CH 3 Z is -CI- 2 C(O)-,n .25 is 1, and p is 1, then W, together with CH and C does not form an 2, 3-dihydro- Il-(t-butylC(O)CH 2 )-5-(2-pyridyJ)- 1 H- l, 4 -benzodiazepin-2-one; I when R' is 4 -ethoxyphenyl, 2 4 6 -trimethylphenyl,
4-phenyiphenyl, CH 3 OC(O)CH 2 4-HOCH 2 -phenyl, 2,4, 6 -trifluorophenyl, 2 -trifluoromethyl- fluorophenyl, or CH 3 R 2 is -CH 3 Z is n is 1, and p is 1, then W, together with >CH and does not form a 2 ,3-dihydro-l-(NN- Sdiethylamno-CHCH 2-)5..(2-pyridy H-i 1. 4 -benzodiazepin-2.-one; 744 3. when R' is 2,6-difluorophenyl, R 2 is -CH 3 Z is -CH(OH)C(O>- n is 1, and p is 1, then W, together with CH and C does not formn a 2 ,3-dihydro-l1-(NN-diethylamino-CH 2 CH2)5..(2.pyridyl)
18-1,4- benzodiazepin-2-one, K. when nis1, then w C 11 x does not equal cycloalcyl of from 3 to 8 carbon atoms optionally substituted with 1 to 3 alkyl groups L. when n is 0 an W- together with IS a nitrogen heterocycle .having 5 through 7 ring atoms, one of which is nitrogen and the remainder of which are carbon wherein X is oxo, then R' is not alkyl substituted with -C(O)NHOHI- 744A 2. A method for preventing the onset of AD in a human patient at risk for developing AD which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I: W Rl V Z NH C(H) m Ci C 0* 745 wherein R' is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic; W, together with forms a cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl, or substituted cycloalkenyl group wherein each of said cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl or substituted cycloalkenyl group is optionally fused to form a bi- or multi-fused ring system (preferably no more than 5 fused rings) with one or more ring structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group which, in turn, each of such ring structures are optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, nitro, cyano, carboxyl, carboxyl esters, alkyl, substituted S 15 alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, N- alkylamino, N,N-dialkylamino, N-substituted alkylamino, N-alkyl N-substituted alkylamino, N,N-disubstituted alkylamino, -NHC(O)R 4 -NHSO,R 4 -C(O)NH,, -C(O)NHR 4 -C(O)NR 4 R 4 -S(O)R 4 -S(O) 2 R 4 -S(O),NHR 4 and -S(O),NR 4 R' where each R 4 is independently selected from the group consisting of alkyl, substituted alkyl, or aryl; X is selected from the group consisting of oxo thiooxo hydroxyl thiol and hydro Y is represented by the formula: R2 I I UP 746 wherein each R 2 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl cycloalkyl, aryl, heteroaryl and heterocyclic; Z is represented by the formula where T is selected from the group consisting of a bond covalently linking R' to oxygen, sulfur, -NR 5 where R 5 is hydrogen, acyl, alkyl, aryl or heteroaryl group; X' is hydrogen, hydroxy or fluoro, X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group; with the proviso that when T is oxygen, sulfur or NR 5 then X' and X" are each hydrogen; mis 1; n is an integer equal to 0, 1 or 2; p is an integer equal to 0 or 1 such that when p is zero, the ring defined by W and is unsaturated at the carbon atom of ring attachment to Y and when p is one, the ring is saturated at the carbon atom of ring attachment to Y, with the following provisos: A. when R' is 3 ,5-difluorophenyl, R 2 is -CH3, Z is n is 1, and p is 1, then W, together with >CH and does not form a 2- (S)-indanol group; 'i B. when R' is phenyl, R' is -CH 3 Z is n is 1, and p is 1, then W, together with >CH and does not form a trans-2-hydroxy- cyclohex-1-yl group; C. when R' is phenyl, Z is -CH 2 n is 0, and p is 1, then W, together with >CH and does not form a gammabutyrolactone group or a 5,5-dimethyl-gammabutyrolactone group; D. when R' is phenyl, Z is -CH 2 n is 0, and p is 1, then W, together with CH and C=X, does not form a e-caprolactam group; E. when R' is cyclopropyl, R 2 is -CH 3 Z is n is 1, ST4 and p is 1, then W, together with CH and C=X, does not form an N- Smethylcaprolactam group; 747 F. when R' is 4-chlorobenzoyl-CH 1 RI is -CH 3 Z is -CH 2 n is 1, and p is 1, then W, together with CH and C does not form an 2, 3-dihydro-l1-methyl-5-phenyl- 1H-i 4 -benzodiazepin-2-one; G. when R' is 2-phenyiphenyl, RI is Z is -CH 2 nz is 1, and p is 1, then W, together with CH and C does not form an 7- methyl-S 7 -dihydro-6H-dibenz[b,d]azepi-6-one; H. when RI is CH 3 OC(O)CH 2 R 2 is -CH 3 Z is -CH 2 n is 1, and p is 1, then W, together with CH and C does not form an 2 ,3-dihydro-l1-(t-butyIC(O)CH 2 -)-5-(2pyridyI> 1 H-1I, 4 -benizodiazepin-2-one, 1. when R 1 is 4-ethoxyphenyl, 2 4 6 -trixnethylphenyl, 4-phenyiphenyl, CH 3 OC(O)CH2-, 4-HOCH 2 -pheny 1, 2,4, 6-trifluorophenyl, 2-trifluoromethy 1-4- fluorophenyl, or CH 3 R 2 is -CH3, Z is n is 1, and p is 1, then W, together with CH and C does not formn a 2,3-dihydro- N- d iethylaxnino-CHCH 2 (2-pyrdyl 1 H-i1, 4 -benzodiazep in-2 -one; J. when R' is 2 ,6-difluorophenyl, R2 is -CH 3 Z is -CH(OH)C(O)-, :n is 1, and p is 1, then W, together with CH and C does not :::form a 2 ,3-dihydro- 1 NdiethyaminoCH, CH pyridy1)- 1 H- 1, 4- benzodiazepin-2-one, K. when nis1, then *S T wihItw ly rus 747A L. when n is 0 an W- together with is a nitrogen heterocycle having 5 through 7 ring atoms, one of which is nitrogen and the remainder of which are carbon wherein X is oxo, then R' is not alkyl substituted with -C(O)NHOH-. es 0@SO ~'0Oe 0 *0S9 S *0 0S@S S. S S 0 S. S 0S 0 S. S. 6 S 6@*0 S S. S 5* 0 748 3. A method for treating a human patient with AD in order to inhibit further deterioration in the condition of that patient which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I: R NH C (H)p rn n C /x wherein R' is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted S: alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic; W, together with forms a cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl, or substituted cycloalkenyl group wherein each of said cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl or substituted cycloalkenyl group is optionally fused to form a bi- or multi-fused 30 ring system (preferably no more than 5 fused rings) with one or more ring structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group which, in turn, each of such ring structures are optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkoxy, thioalkoxy, stituted thioalkoxy, nitro, cyano, carboxyl, carboxyl esters, alkyl, substituted a 1, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, N- 749 alkylaniino, N, N-dialkylamino, N-substituted alkylamino, N-alkyl N-subsiwted alkylamino, N,N-disubstimuted alkylamnino, -NHC(O)R 4 -NHSO 2 -C(O)NH 2 -C(O)NHR 4 -C(O)NR 4 R 4 -S(O)R 4 -S(O) 2 R 4 -S(O)2NHR 4 and -S(O) 2 NR 4 R 4 where each R 4 is independently selected from the group consisting of alkcyl, substituted ailkyl, or aryl; X is selected from the group consisting of oxo thiooxo hydroxyl thiol and hydro (11,H); Y is represented by the formula: F 0 wherein each R' is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalky!, aryl, heteroaryl and heterocyclic; Z is represented by the formula -T-CX'XC(O). where T is selected from the group consisting of a bond covalently linking RI to -CX'X" oxygen, :sulfur, -NR' where RS is hydrogen, acyl, alkyl, aryl or heteroaryl group; X' is hydrogen, hydroxy or fluoro, X" is hydrogen, hydroxy or fluoro, or X' and XV together form an oxo group; with the proviso that when T is oxygen, sulfur or NR 5 then Xand X" are each hydrogen; M is 1; 749A n is an integer equal to 0, 1 or 2; p is an integer equal to 0 or 1 such that when p is zero, the ring defined by W and is unsaturated at the carbon atom of ring attachment to Y 750 and when p is one, the ring is saturated at the carbon atom of ring attachment to Y, with the following provisos: A. when RI is 3 ,5-difluorophenyl, R 2 is -OH 3 Z is -CH 2 0 n is 1, and p is 1, then W, together with CH and >OC= X, does not form a 2- (S)-indanol group; B. when R' is phenyl, R' is -OH 3 Z is -CH 2 n is 1, and p is 1, then W, together with OH and C does not form a trans-2-hydroxy- cyclohex-1-yl group; when R' is phenyl, Z is -CH 2 n isO0, and p is 1, then W, together with CH and >0C X, does not form a gammaburyrolactone group or a 5,5-dimethyl-gamxnabutyrolactone group; D. when R' is phenyl, Z is n isO0, and p is 1, then W, together with OH and C does not form a e-caprolactam group; when R' is cyclopropyl, R' is -OH 3 Z is .n is 1, and p is 1, then W, together with >01CH and C does not form an N- mnethylcaprolactarn group; F. when RI is 4-chlorobenzoyl-CH,.., R 2 is -OH 3 Z is -CH 2 n is 1, and p is 1. then W, together with CH and C does not form an 2 ,3-dihydro- 1 -methyl-5 -pheny I- 1H- 1, 4 -benzodiazepin-2 -one; G. when R' is 2 -phenylphenyl, R2 is -OH 3 Z is n is 1, and p is 1, then W, together with CH and C does not form an 7- methyl-5, 7-dihydro-6H-dibenzjb ,d)azepin-6-one; H when R' is 0H 3 00(O)CH 2 R2 is -OH 3 Z is -0H 2 n 25 is 1, and p is 1, then W, together with >OCH and >OC= X, does not form an 3-dihydro- 1 (r-buty1CO)CH 2 -)-5-(2-pyridy 1 H- 1, 4 -benzodiazep in-2 -one; I. when R' is 4 -ethoxyphenyl, 2 4 ,6-trimethylphenyl, 4-phenyiphenyl, CH 3 00(0)OH,-, 4-HOOH 2 -phenyl, 2,4, 6-trifluorophenyl, 2 -trifluoromethyl-4- fluorophenyl, or CH 3 R' is -OH 3 Z is n is 1, and p is 1, then W, together with >OCH and >OC= X, does not form a 2,3 -dihydro- I -(NN- diethylamino-OCH 2 -)5.(2-pyridyl) 1 H-i 4 -benzodiazepin-2-one; 751 J. when R' is 2,6-diifluorophenyl, R 2 is -CH 3 Z is -CH(OH)C(O)-, n is 1, and p is 1, then W, together with CH and C does not form a 2 ,3-dihydro-l1-(NN-diethylanino-CH 2 CH-)-5..(2-pyridyl). 1H-i ,4- benzodiazepin-2-one, K. when nis1, then C II x does not equal cycloalkyl of from 3 to 8 carbon atoms optionally substituted with i to 3 alkyl groups, L. when n is 0 an W- together with is a nitrogen heterocycle having 5 through 7 ring atoms, one of which is nitrogen and the remainder of which are carbon wherein X is oxo, then R1 is not alkyl substituted with -C(O)NHOH-. 4. A method according to Claim 3 wherein R' is aryl or heteroarYl. A method according to Claim 4 wherein R' is selected from the group consisting of phenyl, 30 a substituted phenyl group of the formula: Rb' Rc 752 wherein R' is selected from the group consisting of acyl, alkyl, alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, and wherein Rb and R' are fused to form a heteroaryl or heterocyclic ring with the phenyl ring wherein the heteroaryl or heterocyclic ring contains from 3 to 8 atoms of which from 1 to 3 are heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur Rb and Rb' are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy, and thioalkoxy with the proviso that when R' is hydrogen, then Rb and R b are either both hydrogen or both substituents other than hydrogen, 2-naphthyl, 2-naphthyl substituted at the 4, 5, 6, 7 and/or 8 positions with 1 to substituents selected from the group consisting alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, thioalkoxy, aryl, and heteroaryl, 15 heteroaryl, and S(f) substituted heteroaryl containing 1 to 3 substituents selected from the *group consisting of alkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl, thioalkoxy, thioaryloxy provided that said substituents are not ortho to the heteroaryl attachment to the -NH group. 6. The method according to Claim 4 wherein R' is selected from the group consisting of mono-, di- and tri-substituted phenyl groups. 7. The method according to Claim 6 wherein R' is a disubstituted 25 phenyl selected from the group consisting of 3 ,5-dichlorophenyl, difluorophenyl, 3 ,5-di(trifluoromethyl)-phenyl, 3,4-dichlorophenyl, 3,4- *difluorophenyl, 3 -(trifluoromethyl)-4-chlorophenyl, 3 -chloro-4-cyanophenyl, 3- chloro-4-iodophenyl, and 3 4 -methylenedioxyphenyl. 8. The method according to Claim 6 wherein R' is a monosubstituted RA/ phenyl selected from the group consisting of 4 -azidophenyl, 4-bromophenyl, 4- 753 chioropheny I, 4-cyanophenyl, 4 -ethylphenyl, 4 -fluorophenyl, 4 -iodophenyl 4- (phenylcarbonyl)-phenyl, and I-ethoxy)ethylpherwl. 9. The method according to Claim 6 wvherein R' is a trisubstituted phenyl selected from the group consisting of 3 4 ,5-trifluorophenyl and 3,4,5- trichiorophenyl. The method according to Claim 4 wherein RI is selected from 2- naphthyi, quinolin-3-yl, 2 -methylquinolin-6-yl, benzothiazol-6-yI, 5-indolyl, and phenyl. 11. A method according to any one of claims 1, 2 or 3 wherein R' is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, 2-chlorophenyl, 2- fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methyiphenyl, 2-methoxyphenyl, 2 -phenoxyphenyl, 2 -trifluoromethylphenyl, 4-fluorophenyl, 4- 9. chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methyiphenyl, 4-hydroxypheny 1, 4-methoxyphenyl, 4-ethoxyphenyl, 4 -butoxyphenyl, 4 -iso-propylphenyl, 4- phenoxyphenyl, 4 -trifluoromethylphenyl, 4 -hydroxymethylphenyl, 3- methoxyphenyl, 3-hydroxyphenyl, 3 -nitrophenyl, 3-fluorophenyl, 3- chiorophenyl, 3-bromophenyl, 3 -phenoxyphenyl, 3 -thiomethoxyphenyl, 3- methyiphenyl, 3 -trifluoromethylphenyl, 2, 3 -dichlorophenyl, 2 ,3-difluorophenyl, 2 ,4-dichlorophenyl, 2 ,S-dimethoxyphenyl, 3, 4-dichiorophenyl, 3,4- difluorophenyl, 3 4 -methylenedioxyphenyl, 3 4 -dimethoxyphenyl, 9* difluorophenyl, 3, 5-dichlorophenyl, 3 ,5-di-(trifluoromethyl)phenyl, dimethoxyphenyl, 2 ,4-dichlorophenyl, 2, 4 -difluorophenyl, 2, 6-difluorophenyl, 3,4 ,S-trifluorophenyl, 3,4, S-trimethoxyphenyl, 3,4 ,S-tri-(trifluoromethyl)phenyl, 2, 4,6-trifluorophenyl, 2,4 6 -timethylphenyl, 2,4, 6 -tri-(trifluoromethyl)phenyl, 2,3 ,5-trifluorophenyl, 2,4 ,S-trifluorophenyl, 2, 5-difluorophenyl, 2-fluoro-3- RAj trifluoromethyiphenyl, 4 -fluoro-2-trifluoromethylphenyl, 2-fluoro-4- 754 trifluoromethyiphenyl, 4 -benzyloxyphenyl, 2 -ch-doro-6-fluorophenyl, 2-fluoro-6- chlorophenyl, 2,3,4,5, 6 -pentafluorophenyl, 2. S-dimethylphenyl, 4- phenyiphenyl, 2 -fluoro- 3 -trifluoromethylphenyl, adamantyl, benzyl, 2- phenylethyl, 3 -phenyl-n-propyl, 4 -phenyl -n-butyl, methyl, ethyl, n-propyl, iso-propyl, iso-butyl, sec-butyl, tent-butyl, n-pentyl, iso-valeryl, n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopent-l1-enyl, cyclopent-2- enyl, cyclohex-l1-enyl, -CH,{-cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclohexyl, -CH 2 -cyclopentyl, -CH 2 CH 2 -CYclopropyl, -CHCH 2 -cyclobutyl, -CH 2 CH 2 -dyclohexyl, -CI{,CH2-CYClopentyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3-yl), chioropyridyls (including chloropyrid-3-yI), thien-2-yl, thien-3-yl, benzothiazol-4-yl, 2 -phenylbenzoxazo.. furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl, thionaphthen-3 -yI, thionaphthen-4-yl, 2 -chlorothiophen-5.yl. 3 6 -methoxythionaphthen-2-yI, 3 -phenyl- 1,2,4- thiooxadiazol-5-yl, 2 -phenyloxazol.4-yI, indol-3-yl, 1 -phenyl-tetraol-5-yl, allyl, 2 -(cyclohexyl)ethyl, (CH 3 )2CH =CHCHCHCH(CH 3 OC(O)CH,-, thien-2-yl- methyl, 2 -(thien-2-yl)ethyl, 3 -(thien-2-yl)-n-propyl, 2 4 -nitrophenyl)ethyl, 2 4 -methoxyphenyl)ethyl, norboran-2-yl, 4 -methoxyphenyl)methyl, (2- *.methoxyphenyl)methyl, 3 -methoxypiienyl)methyl, 3 -hydroxyphenyl)methyl, 4 -hydroxyphenyl)methyl, 4 -methoxyphenyl)methyl, 4 -methylphenyl)methyl, 4 -fluorophenyl)methyl, 4 -fluorophenoxy)methyl, (2 4 -dichlorophenoxy)ethyl, 4 -chlorophenyl)methyl, 2 -chlorophenyl)methyl, (1 -phenvl)ethy!, (1 :chlorophenyl)ethyl, (1 -trifluoromethyl)ethyl, 4 -niethoxyphenyl)ethyl, CH 3 OC(O)CH 2 benzylthiomethyl, S-(methoxycarbonyl)-n-pentyl, 3- (methoxycarbonyl)npropyl, indan-2-yI, 2 -methylbenzoffran3yl), methoxymethyl, CH 3 CH CH 3 CH 2 CH 4clrpey)(CH- 4 -fluorophenyl)C(O)CH 2 4 -methoxyphenyl)C(o)Cj{,-, 4 -(fluorophenyl)- NHC(O)CH 2 l-phenyl-n-butyl, (0) 2 CHNHC(O)CH 2 CH 2 ,1 (CH 3 )2NC(O)CH, 2 CHNHC(O)CH,CH 2 methylcarbonylmethyl, (2,4- dirnethylphenyl)C(o)CHz- 4 -methoxyphenyl-C(O)CH,-, phenyl-C(O)CH 2 I P-4 Qz CH 3 ethenyl, methythiomethyl, (CI 3 3 CNIC(O)CH 2 755 4-fluorophenyl-C(O)C 2 diphenylmethyl, phenoxymethyl, 3,4- methylenedioxyphenyl-CH, benzo[b] thiophen-3-yl, (CI- 3 3 COC(O)N}ICH2-, trans-styryl, H 2 NC(O)CH- 2 CfI 2 2 -trifluorornethylphenyl..C(O)CH, OC(O)NHCH(46)CH 2 mesityl, CH 3 CH( =NHOH)C11 2 4-Cfl 3 NHC(O)CH 2 CH 2 OC(O)CH()CH 2 (CH 3 )2CHC(O)NHCH()- CH 3 CH 2 OCH 2 CH3OC(O)CH(CH 3 )(CH3- 2 2 ,2-trifluoroethyl, 1 -(trifluoromethyl)ethyl, 2 -CH- 3 ,benzofuran-3-yl, 2-(2 4 -dichlorophenoxy)ehyl, OS0 2 CH 2 3 -cyclohexyl-n-propyl, CF 3 CH 2 CH 2 CH 2 and N-pyrrolidinyl. 12, A method according to anyone of Claims 1, 2 or 3 where n is one or two, and each RI is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic. 13. The method according to Claim 12 wherein R 2 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, -CH 2 CH(CH 2 CH 3 2 2-methyl-n-butyl, 6 -fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl, -CH 2 -cyclopropyl, -CH,-cyclohexyl, -CH 2 CH 2 -CYClopropyl, *-CHCH 2 -cyclohexyl, -CH 2 -indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxypheny 1, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH 3 2 NCH 2 CHCH 2 beIz, *p-(CH 3 3 COC(O)CH 2 -bnzy, p-(HOOCCH 2 O)-benzyl, 2 -aminopyrid-6-yl, p-(N-morpholino-CH 2 CH 2 o)-benyl -CH,CH 2 C(O)NH 2 -CH 2 -imidazol-4-yl, 25 -CH2-(3-tetrahydrofuranyl), -CH 2 -rthiophen-2-yl, -CH 2 1-methyl)cyclopropyl, :-CH,-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, -CH,-C(O)O-t-butyl, CH 2 -C(CH 3 3 -CH 2 CH(CH 2 CH 3 2 2 -methylcyclopentyl, cyclohex-2-eny 1, -CH[CH(CH 3 )JCOOCH 3 -CH 2 CH 2 N(CH 3 2 -CH 2 C(CH 3 =CH 2 -CH 2 GH=CHCH 3 (cis and trans), -CI1 2 0H, -CH(OH)C11,, -CH(O-t-butyl)CH 3 -Q'CH 2 CH 3 -(CH 2 ),NH-Boc, -(C11 2 4 NH 2 -CH 2 -pyridyl, pyridyl, 756 -C11 2 -naphthyl, -CH 2 -(N-morpholino), p-(N-morpholino-CH 2 CH 2 oy-bezyl, benzofbjthiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7- tetrahy'drobenzobthiophen2yl, benzofblthiophen-3-yl, chlorobenzofblthiophen3yl, bernzo[bjthiophen-5.yl, 6 -methoxynaphth-2-y1 -CI-,CH 2 SCII 3 thien-2-yl, thien-3-yl, 14. A method according to any one of Claims 1, 2 or 3 wherein the cyclic groups defined by W and is selected from the group consisting of lactones, lactams, thiolactones, thiolactams, heterocyclic and cycloalcyl groups. The method according to Claim 14 wherein the cyclic group defined by W and forms a lactamn or thiolactamn ring of the formula: **ee -C(H)p T S /71 757 wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -KR 2 Z)qR 2 1- and _ZR 21 where Z is a substituent selected from the group consisting of and NR 20 each R" 0 is independently selected from the group consisting of alkyl, alkenyl, ailcnyl, cycloallcyl, cycloalkenyl, substituted ailkyl, substituted alkenyl, substituted alynyl, aryl, heteroaryl and heterocyclic, each R 2 1 is independently alkylene, substituted ailcylene, alkenylene and substituted ailcenylene with the proviso that when Z is or any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3. 16. The method according to Claim 15 wherein the cyclic group defined by W together with is selected from the group consisting of: (Ra)w N R N*'R 0 0 (Ra) 25 I NN 0 Rb 0 Rb 758 Ra NN 0 ,R N 00 (V)Mt I Ra N-..Rb N 0 *BB(Ra)w (Ra) w 2 0 0Nb N 0 Rb R 759 (Ra) w (Ra)w N o Rb (Ra)w N o Rb Rb 0* Rb 07 N Rb N N Re Re :o -Z N 0Ob \N N 760 wherein A-B is selected from the group consisting of alkylene, alkenylene, substituted alkylene, substituted alkenylene and Q' is oxygen or sulfur; each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like; R' is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; Rb is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, heteroaryl, hererocyclic, and the like; Re is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl, and substituted cycloalkyl; t is an integer from 0 to 4; t' is an integer from 0 to 3; and w is an 15 integer from 0 to 3. 17. The method according to Claim 14 wherein the cyclic group defined by W, together with is a ring of the formula: T -C(H)p g CH OH 30 OH 761 or T -C(H)p CH SH wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R 2 and -ZR"- where Z is a substituent selected from the group consisting of and 20 NR 20 each R 2 0 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 2 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is or any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3. 762 The method according to Claim 17 wherein the alcohol or thiol subs tituted groups is selected from the group consisting of MV) (Ra)w OH OH (V)t (V)t HO (Ra). Mt) 09.0 V906*S 0 *00 0055 *00 0006 so* wherein each V is independently selected from the group consisting of hydroxy, 20 acyl, acyloxy, alkyl, substituted ailkyl, alkoxy, substituted alkoxy, alkenyl, substituted ailcenyl, ailcynyl, substituted alkynyl, amino, aminoacyl, alkaryl. aryl, aryloxy, carboxyl, carboxylalcyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioallcoxy, trihalomethyl and the like; R' is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; t is an integer from 0 to 4; and w is an integer from 0 to 3.
19. The method according to Claim 1 4 wherein the cyclic group defined by W, together with forms a ring of the formula: 763 T- -C(H)p NR2O CH 2 wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R 21 Z),RI- and -ZR 1 where Z is a substituent selected from the group consisting of and NR 2 0 each R" 2 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 2 is independently 20 alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is or any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3.
20. The method according to Claim 14 wherein the cyclic group defined by V, together with forms a ring of the formula: T *T T .i -C(H) 0 I 0 764 wherein p is zero or one, T is selected from the group consisting of ailkylene, substituted alkylene, alkenylene, substituted alkenylene, 2 Z)qR_, 1 and -ZR 2 I- where Z is a substituent selected from the group consisting of and NR 20 each R 2 is independently selected from the group consisting of alkyl. alkenyl, ailcynyl, cycloallcyl, cycloalkenyl, substituted alkyl, substituted alkenyl. substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is or any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3.
21. The method'according to Claim 20 wherein the compound of formula I is selected from the group consisting of *(Ra)w (Ra)w 0 0 250 w h e ei ea h V i n e e d n l e e t d f o m t e g o p c n i t n f h d o acl .cloy alyl 0usiue lyakxsbtttdakxakn s u s i u e e y a k n l u s i u e l y n l m n a n n a y a k r l ar*oy cabxl.abxllycanhlnto eeor al o y su si ue..o l o y -h l m th l a d t e lk R s s l c e 765 from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; t is an integer from 0 to 4; and w is an integer from 0 to 3.
22. The method according to Claim 14 wherein the cyclic group defined by W, together with forms a ring of the formula: T -C(H)p C S 0 wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R 21 Z)R 2 and -ZR 1 where Z is a substituent selected from the group consisting of and NR 2 each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, .i substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the 30 proviso that when Z is or any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3.
23. 2 The method according to Claim 14 wherein the cyclic group defined by W, together with forms a ring of the formula: 766 T C(H)p C/o 0 0 0000 0 oo o o". .o. wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R 2 and -ZR 21 where Z is a substituent selected from the group consisting of and NR 2 0 each R 2 0 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R" is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is or any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3.
24. The method according to Claim 14 wherein the cyclic group defined by W, together with forms a ring of the formula: 0 %s^ T I I S 767 wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R 2 Z)qR, and -ZR: 1 where Z is a substituent selected from the group consisting of and NR 2 each R 2 0 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 2 1 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is or any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3. The method according to Claim 14 wherein the cyclic group defined by W, together with forms a ring of the formula: 0 .wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R"Z)qR 2 and -ZR 2 where Z is a substituent selected from the group consisting of and NR 20 each R 2 0 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 2 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the /P 35 proviso that when Z is or any unsaturation in the alkenylene and 768 substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3.
26. The method according to Claim 25 wherein the compound of formula I is selected from the group consisting of: (v)t S(V)t (Ra O c
27. The method according to Claim 14 wherein the cyclic group defined by W, together with forms a ring of the formula: 769 -C(H) C S wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R 2 Z),R 2 and -ZR 21 where Z is a substituent selected from the group consisting of and NR 2 0 each R 2 0 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 2 1 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is or any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3. 28 The method according to Claim 14 wherein the cyclic group defined by W, together with forms a ring of the formula: T -C(H)p SH SH 770 wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R 21 Z)qR 2 1- and -ZR 2 where Z is a substituent selected from the group consisting of and NR 2 0 each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 2 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is or any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3.
29. The method according to Claim 14 wherein the cyclic group defined by W, together with forms a ring of the formula: *20 -C(H) H NR20R20 S. 3 0 wherein p is zero or one, T is selected from the group consisting of alkylene, NR 2 each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, S substituted alkynyl, aryl, heteroaryl and heterocyclic, each R21 is independently ikylene, substituted alkylene, alkenylene and substituted alkenylene with the 771 proviso that when Z is or any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3.
30. A pharmaceutical composition comprising a pharmaceutically inert carrier and a pharmaceutically effective amount of a compound of formula I: R Z NH C(H) mn c C 20 X X wherein R' is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic; W, together with forms a cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl, or substituted cycloalkenyl group wherein each of said cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl or substituted cycloalkenyl group is optionally fused to form a bi- or multi-fused ring system (preferably no more than 5 fused rings) with one or more ring structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group which, in turn, each of such ring structures are optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkoxy, thioalkoxy, A substituted thioalkoxy, nitro, cyano, carboxyl, carboxyl esters, alkyl, substituted ealkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, N- S~0i alkylamino, N,N-dialkylamino, N-substituted alkylamino, N-alkyl N-substituted 772 alkylamino, N,N-disubstituted alkylamnino, -NHC(O)R 4 -NH-S0 2 R, -C()NH 2 -C(O)NHR 4 -C(O)NR 4 R 4 -S(O)R 4 4 -S(O) 2 NHR 4 and -S(0) 2 NR 4 R 4 where each R 4 is independently selected from the group consisting of alkyl, substituted ailkyl, or aryl; X is selected from the group consisting of oxo thiooxo hydroxyl thiol and hydro Y is represented by the formula: R wherein each RI is independently selected from the group consisting of alky), substituted alkyl, alkenyl, substituted ailcenyl, alkynyl, substituted alkynyl, cycloaly, aryl, heteroaryl adheterocyclic; Z is represented by the formula where T is selected from the group consisting of a bond covalently linking R' to oxygen, sulfur, -NR' where R' is hydrogen, acyl, alkyl, aryl or heteroaryl group; is hydrogen, hydroxy or fluoro, X" is hydrogen, hydroxy or fluoro. or >2 and XV together form an oxo group; with the proviso that when T is oxygen, sulfur or NR 5 then X and XV are each hydrogen; M misl1; 772A n is an integer equal to 0, 1 or 2; p is an integer equal to 0 or 1 such that when p is zero, the ring defined by W and is unsaturated at the carbon atom of ring attachment to Y and when p is one, the ring is saturated at the carbon atom of ring attachment to Y, with the following provisos: *9 a a a RA/, -7O >1J 773 A. when R' is 3 ,5-difluoropheny1, R 2 is -CH 3 Z is -CH2C(O)., n is 1, and p is 1, then W, together with CH and C does not form a 2- (S)-indanol group; B. when R' is phenyl, R 2 is -CH 3 Z is n is 1, andp is 1, then W, together with CH and C does not form a trans-2-hydroxy- cyclohex- 1-yJ group; C. when R' is phenyl, Z is -CH 2 n isO0, and p is 1, then W, together with CH and C does not form a gamlnabutyrolactone group or a 5, S-dixnethyI-gammabutyrolactone group; D. when RI is phenyl, Z is -CH 2 n is 0, and p is 1, then W, together with CH and C does not formn a e-capro~lactam group; E. when R' is cyclopropyl, R 2 is -CH 3 Z is -CH 2 'n is 1. and p is 1, then W, together with CH and C does not form an N- methylcaprolactam group; S* 15 F. when R' is 4 -chlorobenzoy-CH,-. R 2 is -CH 3 Z is -CHC(O)-, goof cost n is 1, and p is 1, then W, together with CH and C does not form an 2, 3-dihydro- 1 -methyl-5-pheny 1- 1 H-i1, 4 -benzodiazepin-2 -one; G. when R' is 2 -phenylphenyl, R 2 is -CH 3 Z is n is 1, and p is 1, then W, together with CH and C does not form an 7- methyl- 7 -dibydro-6H-diberiz[,d~azepin6one; H. when R' is CH 3 OC(O)CH 2 R 2 is Z is fl is 1, and p is 1, then W, together with CH and C does not form an 3-dihydrol-tutl()H---2prd)- 1 H- 1, 4 benzodiazep in-2 -one; 0 I. when R' is 4 -ethoxyphenyl, 2 4 6 -trixnethylphenyl, 4-phenylphenyl, 00.0 t 25 CH 3 OC(O)CH,-, 4 -HOCH 2 -phenyl, 2,4, 6 -trifluorophenyl, 2 -trifluqromethyl-4- fluorophenyl, or CH 3 R' is -CH 3 Z is -CH 2 n is 1, and p is 1, OCS* then W, together with >CH and does not form a 2,3-dihydro-l-(NN diethylmmio-CHCH 2 -)5-(2pyridyl)ylH1, 4 -benzodiazepin-2-one; J. when R' is 2 ,6-difluorophenyl, R 2 is -CH 3 Z is -CH(OH)C(O)-, ,~0RQ n is 1, and p is' 1, then W, together with CH and>C=Xdeno 774 form a 2,3-dihydro-1-(NN-diethylamino-CH 2 CH 2 -)-5-(2-pyridyl) 1H-1,4- benzodiazepin-2-one, K. when n is 1, then -C(H)p W C 11 I I does not equal cycloalkyl of from 3 to 8 carbon atoms optionally substituted with 1 to 3 alkyl groups, L. when n is 0 an W- together with is a nitrogen heterocycle having 5 through 7 ring atoms, one of which is nitrogen and the remainder of which are carbon wherein X is oxo, then R' is not alkyl substituted with -C(O)NHOH-. M. when n is 0 and -C(H)p together with forms a fused ring benzolactam in with the lactam nitrogen is substituted with an optionally substituted phenyl, biphenyl, phenylalkylene or biphenylalkylene substituent, and T is a bond then R, is not aminoalkylene or substituted aminoalkylene. N. W together with does not form a substituted or unsubstituted azetidinone. P.%OPER\MaI2OOW~7OO)7-qS spe'JP2\7007-9A spe.dmo~.lm/12 774A 3. The pharmaceutical composition according to Claim 30 wherein R1 is aryl or heteroaryl.
32. The pharmaceutical composition according to Claim 31 wherein R' is selected from the group consisting of phenyl, 775 a substituted phenyl group of the formula: Rb Rc Rb wherein Rc is selected from the group consisting of acyl, alkyl, alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, and wherein Rb and RC are fused to form a heteroaryl or heterocyclic ring with the phenyl ring wherein the heteroaryl or heterocyclic ring contains from 3 to 8 atoms of which from 1 to 3 are heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur R b and R b are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy, and thioalkoxy with the proviso that when R' is hydrogen, then R' and Rb' are either both hydrogen or both substituents other than hydrogen, 2-naphthyl, 25 2-naphthyl substituted at the 4, 5, 6, 7 and/or 8 positions with 1 to substituents selected from the group consisting alkyl, alkoxy, halo, cyano, nitro, S.o. trihalomethyl, thioalkoxy, aryl, and heteroaryl, heteroaryl, and substituted heteroaryl containing 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro,'heteroaryl, thioalkoxy, thioaryloxy provided that said substituents are not ortho to the heteroaryl attachment to the -NH group. 776
33. The pharmaceutical composition according to Claim 30 wherein RI is selected from the group consisting of mono-, di- and tni-substituted phenyl groups. 1 The pharmaceutical composition according to Claim 33 wherein R' is a disubstituted phenyl selected from the group consisting of dichlorophenyl, 3, 5-difluorophenyl, 3, S-di(trifluoromethyl).phenyl, 3,4- dichiorophenyl, 3 ,4-difluorophenyl, 3 -(trifluoromethyl)-4-chlorophenyl, 3- chloro-4-cyanophenyl, 3-chloro-4-iodophenyl, and 3 4 -methylenedioxyphenyl. The pharmaceutical composition according to Claim 33 wherein R' is a monosubstituted phenyl selected from the group consisting of 4-azidophenyl, 4-brornophenyl, 4-chiorophenyl, 4 -cyanophenyl, 4-ethylphenyl, 4-fluorophenyl, 4-iodophenyl, 4 -(phenylcarbonyl)-phenyl, and 1- ethoxy)ethylphenyl. :36. The pharmaceutical composition according to Claim' 33 wherein R' is a trisubstituted phenyl selected from the group consisting of 3,4.5- trifluorophenyl and 3,4, is37 2 .te The pharmaceutical composition according to Claim 30 x'herein R' is eletedfrom 2-naphthyl, quinolin-3-yl, 2 -methylquinolin-6..yl, benzothiazol- 6-yl, 5-indolyl, and phenyl. 3. rhe pharmaceutical composition according to Claim 3 0 wherein R' is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, chlorophenyl, 2-fluorophenyl, 2 -bromophenyl, 2-hydroxyphenyl, 2 -Mitrophenyl, 2-methylphenyl, 2 -methoxyphenyl, 2 -phenoxyphenyl, 777 2 -trifluoromethylphenyl, 4 -fluorophenyl, 4 -chlorophenyl, 4 -bromophenyl, 4-nitrophenyl, 4 -methylphenyl, 4 -hydroxyphenyl, 4 -metboxyphenyl, 4-ethoxyphenyl, 4 -butoxyphenyl, 4 -iso-propylphenyl, 4 -phenoxyphenvl, 4 -trifluoromethylphenyl, 4 -hydroxymethylphenyl, 3 -methoxyphenyl, 3-hydroxyphenyl, 3 -nitrophenyl, 3 -fluorophenyl, 3 -chlorophenyl, 3-bromophenyl, 3 -phenoxyphenyl, 3 -thiomerthoxyphenyl, 3 -methylphenyl, 3 -trifluoromethylphenyl, 2, 3 -dichlorophenyl, 2, 3 -difluorophenyl, 2,4- dichlorophenyl, 2,~ 5 -dixnethoxyphenyl, 3, 4-dichlorophenyl, 3 ,4-difluorophenyl, 3 4 -methylenedioxyphenyl, 3 4 -dimethoxyphenyl, 3 ,S-difluorophenyl, 3, 5-dichiorophenyl, 3 .S-di-(trifluoromethyl)phenyl, 3, S-dimethoxyphenyl, 2 ,4-dichlorophenyl, 2 4 -difluorophenyl, 2, 6 -difluorophenyl, 3,4,5- trifluorophenyl, 3,4, S-trimethoxyphenyl. 3,4, S-tri-(trifluorometh.yl)phenyl, 2,4, 6-trifluorophenyl, 2,4, 6 -trimnethylphenyl, 2,4, 6 -tri-(trifluorornethyl)phenyl, 2,3 ,5-trifluorophenyl, 2 4 ,5-trifluorophenyl, 2, 5-difluorophenyl, 2-fluoro-3- trifluoromethylphenyl, 4 -fluoro- 2 -rtrifluoromettlylphenyl, 2 -fluoro.4- trifluoromethyiphenyl, 4 -benzyloxyphenyl, 2 -chloro-6-fluorophenyl, 2 -fluoro-6- chlorophenyl, 2,3,4,5 6 -pefltafluorophenyl, 2 4 -phenylphenyl, 2 -fluoro-3-trifluoromethylphenyl, adamantyl, benzy I, 2-phenylethyl, 3 -phenyl-n-propyl, 4 -phenyl-n-buryl, methyl, ethyl, n-propyl, iso-propyl, iso-butyl, sec-butyl, teri-buryl, n-penryl, iso-valervi, n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopenryl, cyclopent-lI-enyl, cyclopent-2- enyl, cyclohex-l1-enyl, -C11 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -CYClohexyl, -CH 2 -cyclopentyl, -CH 2 CH- 2 -CYClopropyl, -CH 2 CH 2 -CYClobutyl, -CC2CY'oeyl -HCH-C~opntl pyrid-2-yl, pyrid-3-yI, pyrid-4-yl, fluoropyridyls, chloropyridyls, thien-2-yI, thien-3-yl, benzothiazol-4.yl, 2 -phenylbenzoxazol5yl, furan-2-yl, benzofuran-2-y1, thionaphthen-2-yl, thionaphthen-3-yl, thionaphthen-4yl, 2-chlorothiophen5yl, 3 yl, 2 -(thiophenyl)thien..5.yl, 6 -methoxytllionaphthen-2yl, 3-phenyl-.1 ,2,4- 2 -phenyloxazolA..yl, indol-3-yl, 1 -phenyl-tetraol-5syi, allyl,
300-- 2 -(cyclohexyl)ethyl, (CH 3 )2CH=CHCH2CHCH(CH3)- OC(O)CH 2 thien-2-yl- Tiieihyl, 2 -(thien-2-yl)ethyl, 3 -(thien-2-yi)-n..propyl, 2 4 -nitrophenylpethyl, 778 2-(4-methoxyphenyl)ethyl, norboran-2-yl, 4 -methoxyphenyl)methyl, 2 -methoxyphenyl)methyl, (3-methoxyphenyl)methyl, 3 -hydroxyphenyl)methyl, (4-hydroxyphenyl)methyl, 4 -methoxyphenyl)methyl, 4 -methylpheny l)methyl, (4-fluorophenyl)methyl, (4-fluorophenoxy)methyl, 4 -dichlorophenoxy)ethyl, (4-chloro-;h'enyl)methyl, (2-chlorophenyl)methyl, (1 -phenyl)ethyl, (1 -(p-chlorophenyl)ethyl, (1 -trifluoromethyl)ethyl, 4 -methoxyphenyl)etl, CH 3 OC(O)CH 2 benzylthiomethyl, 3-(methoxycarbonyl)-n-propyl, mndan-2-yl, 2 -methylbenzofuran3yl), methoxymethyl, CH 3 CH CH 3 CH,CH (4-chlorophenyl)C(O)CH 2 (4-fluorophenyl)C(O)C1 2 (4-methoxyphenyl)C(O)CH 2 4 -(fluorophenyl)- NHC(O)CH 2 1 -phenyl-n-butyl, (0) 2 CHNHC(O)CH,CH,. (CH 3 2 NC(O)CH,-, 2 CHNHC(O)CH 2 CHi 2 methylcarbonylmethyl, (2 ,4-dimethylphenyl)C(O)CH 2 4-methoxyphenyl-C(O)CH 2 pheriyl-C(O)CH 2 CH 3 ethenyl, methylthiornetiyl, (CH 3 3 CNHC(O)CH,-, 615 4-fluorophenyl-C(O)CH 2 diphenylmethyl, phenoxymethyl, o~3 ,4-methylenedioxyphenyl-CH 2 benzo[bjthiophen-3-yl, (CH 3 3 COC(O)NHCH 2 o trans-styryi, H 2 NC(O)CH 2 CH 2 2 -tifluoromethylphenyl-C(O)CH2I 0 OC(O)NHCH(,O)CH 2 mesityl, CH 3 CH( =NHOH)CH 2 4-CH 3 NHC(O)CH,CH 2 OC(O)CH(46)CH 2 (CH 3 2 CH 3 CH 2 OCH,-, CH 3 OC(O)CH(CH 3 )(CH 2 3 2,2, 2 -trifluoroethyl, I -(trifluoromethyl)ethyl, 2 -CH 3 -benzofuran-3.yl, 2-(2 4 -dichlorophenoxy)ethyl, OS0 2 CH- 2 3 -cyclohexyl-n-propyl, CFCHCHC 2 adNpyrldy. 2 n r wad ahR s eedetyslcted fro the gpruroisting of :40. The pharmaceutical composition according to Claim 39 wherein is is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, -CH 2 CH(C 2 CH 3 2 2 -methyl-n-butyl, '-K6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, 779 iso-but-2-enyl, 3 -methylpentyl, -CH,-cyclopropyl, -CH 2 -cyclohexyl, -CH,CH 2 cyclopropyl, -CH 2 CH 2 -cyclohexyl, -CH,-indol-3-yl, P-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p- methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p- nitrobenzyl, m-trifluoromethylphenyl, p-(CH 3 )2NCH 2 CH 2 CH 2 O-benzyI, p-(C!H 3 3 COC(O)CH 2 O..benz.yl, p-(HOOCCH 2 O)-benzyl, 2 -aminopyrid.6yl, p-(N-morpholino-CH 2 CH 2 O)-benzyl, -CH 2 CH 2 C(O)NH 2 -CH',-imidazol-4.yl, -CH 2 -(3-tetrahydrofuranyl), -CH 2 -thiophen-2-yl, -CH 2 1-methyl)cyclopropyl, -CH 2 -thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, -CH 2 -C(O)O-t-butyl, -CH 2 -C(CH 3 3 -CH 2 CH(CH 2 CH 3 2 2 -methylcyclopentyl, cyclohex-2-enyl, -CH[CH(CH 3 2 ICOOCH 3 -CHCH 2 N(CH 3 2 -CHC(CH 3 =CH 2 -CH 2 CH=CHCH 3 (cis and trans), -CH,OI-, -CH(OH)CH 3 -CH(O-t-buryl)CH 3 -CH 2 OCH 3 -(CH 2 ),NH-Boc, -(CH 2 ),NH2, -CH2-pyridyl, pyridyl, -CH 2 -naphthyl, -CH 2 -(N-morpholino), p-(N-morpholino-CH,CH 2 O)-benl benzo~blthiophen2yl, 5-chlorobenzo[b]thiophen-2yl, 4,5,6,7- tetrahydrobeno[b]Aophen2yl, benzo thiophen-3-yl, :chlorobenzo[b] thiophen-3-yl, benzo[bthiophen5yl, 6 -methoxynaphth-2.yI, -CH 2 CH 2 SCH 3 thien-2-yl, thien-3-yl 0 41. The pharmaceutical composition according to Claim 30 wherein the cyclic groups defined by W and is selected from the group :::*consisting of lactones, lactams, thiolactones, thiolactams, heterocyclic and cycloalkylgrus 42. The pharmaceutical composition according to Claim 41 wherein the cyclic group defined by W and forms a lactam or thiolactami ring of the formula: -C(H)P T 11-ILNR20 I S wherein p is zero or one, T is selected from the group consisting of alkylene, substituted ailcylene, alkenylene, substituted alkenylene, -(R 21 Z)qR 2 and -ZR 22 where Z is a substituent selected from the group consisting of and each RWO is independently selected from the group consisting of alkyl, alkenyl, alcynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkcynyl, aryl, heteroaryl and heterocyclic, each R 2 2 is independently alkcylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is or any unsaturation in the alkenylene and substituted ailcenylene does not involve participation of the or and q is an integer of from, 1 to 3. 781 43. The pharmaceutical composition according to Claim 42 wherein the cyclic group defined by W together with is selected from the group consisting of: (Ra), N \Rb N\ Rb 0 Rb 0 Rb O *R a N 0 Y Rb N S:o oo 782 Rb (Ra)w 04 *Oe Rb N (Ra)w M .(Ra)w *5 S S *0* *500 S. SP* S 5*55 S. 0 0S 0d OSb* 0 OOS* (Ra)w Rb N 0 Rb Rb 783 Rb Rc 0 N N N N 0b Rb NI Nt *Rc 0 R *wherein A-B Is selected from the group consisting of alkylene, alkenylene, .,.substituted alkylene, substituted alkenylene 'and -N Q' is oxygen or sulfur; each V is independently selected from the group consisting of hvdroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, :substituted alkenyl, alkynyl, substituted ailkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalcyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like; R' is selected from the group consisting of ailkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; R' is selected from the group consisting of ailkyl, substituted alkyl, alkenyl, substituted alkenyl, alicynyl, substituted alkynyl, acyl, aryl, heteroa-yl, heterocyclic, and the like; Rc is selected from the group consisting of ailyl, substituted akIy, alkenyl, substituted alkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl, and substituted ,,cycloancyl; t is an integer from 0 to 4; t' is an integer from 0 to 3; and w is an 7'j nteger,\from 0 to 3. -3,
784-- 4. The pharmaceutical composition according to Claim 41 wherein the cyclic group defined by W, together with is a ring of the formula: T C HD OH or T SH wherein p is zero or one, T is selected from the group consisting of alkylene, substituted ailcylene, alkenylene, substituted alkenylene, -(R 2 Z)qR 2 I and -ZR?4 where Z is a substituent selected from the group consisting of and >N 21 each R" 0 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alicynyl, aryl, heteroaryl and heterocyclic, each R 2 1 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is or any unsaturation in the alkenylene and
785-' substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3. The pharmaceutical composition according to Claim 44 wherein the alcohol or thiol substituted groups is selected from the group consisting of Mt) (Ra)w (Ra)w e S. S OH O wherein each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alicoxy, alkenyl, substituted alkenyl, alcynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like; RI is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; t is an integer from 0 to 4; and w is an integer from 0 to 3. 786 46. The pharmaceutical composition according to Claim 41 wherein the cyclic group defined by W, together with forms a ring of the formula: T wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, 2 and -ZR'- where Z is a substituent selected from the group consisting of and NR 20 each R 2 0 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 2 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is or any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3. 30 47.. The pharmaceutical composition according to Claim 41 wherein the cyclic group defined by W, together with forms a ring of the formula: 787 T -C(H)p C O wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R 21 and -ZR 1 where Z is a substituent selected from the group consisting of and 20 NR 20 each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 2 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is or any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3. 48. The pharmaceutical composition according to Claim 47 wherein the compound of formula I is selected from the group consisting of 788 (V)t (Ra)w (Ra)w, 0 00 0 wherein each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted. alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alcenyl, alkynyl, substituted alkynyl, amino, amninoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like; RI is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; t is an integer from 0 to 4; and w is an integer from 0 to 3. 49. The pharmaceutical composition according to Claim 41 wherein the cyclic group defined by W, together with forms a ring of the 25 T 0 789 wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R 2 Z)qR2,- and -ZR 21 where Z is a substituent selected from the group consisting of and NR 2 0 each R 2 0 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is or any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3. The pharmaceutical composition according to Claim 41 wherein the cyclic group defined by W, together with forms a ring of the formula: -C(H)p C2 *25 S o* wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R 2 Z)4R 2 and -ZR 1 where Z is a substituent selected from the group consisting of and NR, each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R" is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the f e proviso that when Z is or any unsaturation in the alkenylene and 790 substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3. 51. The pharmaceutical composition according to Claim 41 wherein the cyclic group defined by W, together with forms a ring of the formula: T -C(H)p C S S wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R'Z)qR 2 1- and -ZR 2 where Z is a substituent selected from the group consisting of and NR 20 each R 2 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, S. :substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 2 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is or any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the or and q is 30 an integer of from 1 to 3. 52. The pharmaceutical composition according to Claim 41 wherein the cyclic group defined by W, together with forms a ring of the formula: 791 T 100 w herein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R 21 Z)qRI- and -ZR 2 1_ where Z is a substituent selected from the group consisting of and NR 2 0 each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkcynyl, cycloallcyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R" is independently 20 alkylene, substituted alkylene, alkenyl~ne and substituted alkenylene with the proviso that when Z is or any unsaturation in the alkenylene and *substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3. 53. The pharmaceutical composition according to Claim 52 wherein the ~*compound of formula I s selected from the group consisting of: (Ra)w Mt) (Ra)~w 0 0 792 S54. The pharmaceutical composition according to Claim 41 wherein the cyclic group defined by W, together with forms a ring of the formula: T -C(H)p C-C S wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R 21 Z),R 2 and -ZR 2 where Z is a substituent selected from the group consisting of and NR 2 0 each R 2 0 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is or any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3. 793 S The pharmaceutical composition according to Claim 41 wherein the cyclic group defined by W, together with forms a ring of the formula: T C(H) CH SH wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R 21 and -ZR 2 S..where Z is a substituent selected from the group consisting of and NR 2 each R" is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R" is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is or any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3. 794 56. The pharmaceutical composition according to Claim 41 wherein the cyclic group defined by W, together with forms a ring of the formula: -C(H)p 1CH NR 2 0R20 *.oo wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, and -ZR"- where Z is a substituent selected from the group consisting of and NR 2 0 each R' 2 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, S. substituted alkynyl, aryl, heteroaryl and heterocyclic, each R" is independently alkylene, substituted alkylene, alkenylene and substirtted alkenylene with the 30 proviso that when Z is or any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3. 795 57. A compound of formula 1: w R' Z NH Y C(H) p m N C A wherein R' is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, arl, heteroaryl and heterocyclic; W, together with forms a cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl, or substituted cycloalkenyl group wherein each of said cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl or substituted cycloalkenyl group is optionally fused to form a bi- or multi-fused ring system (preferably no more than 5 fused rings) with one or more ring structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic. aryl and heteroaryl group which, in turn, each of such ring structures are optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl. halo, alkoxy, substituted alkoxy, thioalkoxy, *substituted thioalkoxy, nitro, cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, N- alkylamino, N,N-dialkylamino, N-substituted alkylamino, N-alkyl N-substituted alkylamino, N,N-disubstituted alkylamino, -NHC(O)R', -NHSO,R 4 -C(O)NH,, -C(O)NHR, -C(O)NR 4 R 4 -S(O)R 4 -S(O) 2 R 4 -S(0) 2 NHR and -S(0) 2 NR 4 R where each R' is independently selected from the group consisting of alkyl, 7 ,ubstituted alkyl. or aryl; 796 X is selected from the group consisting of oxo thiooxo S), hydroxyl thiol and hydro Y is represented by the formula: R2 C H C NH 0 wherein each R 2 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; Z is represented by the formula where T is selected from 20 the group consisting of a bond covalently linking R' to oxygen, sulfur, -NR 5 where R 5 is hydrogen, acyl, alkyl, aryl or heteroaryl group; X' is hydrogen, hydroxy or fluoro, X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group; 25 with the proviso that when T is oxygen, sulfur or -NR 5 then X' and X" are each hydrogen; m is 1; n is an integer equal to 0, 1 or 2; p is an integer equal to 0 or1 such that when p is zero, the ring defined by W and is unsaturated at the carbon atom of ring attachment to Y and when p is one, the ring is saturated at the carbon atom of ring attachment to Y, with the following provisos: A. when R' is 3,5-difluorophenyl, R 2 is -CH3, Z is n is 1, and p is 1, then W, together with CH and C=X, does not form a 2- (S)-indanol group; 797 B. when R' is phenyl, R 2 is Z is n is 1, and p is 1, then W, together with >CH and does not form a trans-2-hydroxy- cyclohex- 1-yl group; C. when R' is phenyl, Z is -CH 2 n is 0, and p is 1, then W, together with CH and C does not form a gammabutyrolactone group or a 5 ,S-dirnethyl-gammabutyrolactone group; D. when R' is phenyl, Z is -CH 2 n isO0, and p is 1. then W, together with CH and C does not form a c--caprolactam group; E. when R' is cyclopropyl, RI is -CH 3 Z is ,n is 1, and p is 1, then together with CH and C does not form an N- methylcaprolactam group; F. when R' is 4 -chlorobenzoyl-CH,, R' is -CH 3 Z is -CHC(O)-, n is 1, and p is 1, then W, together with CH and C does not form an 2, 3-dihydro- 1 -methyl -5 -pheny I-I 1H- 1, 4 benzodiazep in-2 -one; PO@ 15 G. when R' is 2 -phenylphenyl, R2 is Z is -CH 2 n Sis 1, and p is 1, then W, together with CH and C does not form an 7- methyl-S. 7 -dihydro-6H-dibenz[b azepin-6-one; *SSH. when R' is CI- 3 0C(O)CH 2 R 2 is Z is -CH- 2 n is 1, and p is 1, then W, together with CH and C does not form an 2 ,3-dihydro- 1 -(t-butylC(O)CH 2 )-5-(2-pyridyl)- 1 H-i 1, 4 -benzodiazepin-2 -one; I. when R' is 4 -ethoxyphenyl, 2 4 6 -trimethylphenyl, 4-phenyiphenyl, CH 3 OC(O)CH 2 4-HOCH 2 -phenyl, 2,4, 6-trifluorophenyl, 2 -trifluoromethyl-4- to*fluorophenyl, or CH 3 R' is -CH 3 Z is -CI- 2 n is 1, and pis 1, thnW tgte with >CH and does not form a23dhdol(N n is 1, and p is 1, then W, together with CH and C does not form a 2, 3-dihydro-l1-(NN-diethylamino-CHCH 2 )-5(2-pyridyl) 1 H-i ,4- benzodiazepin-2-one, when n is 1, then 798 -C(H)p C X x does not equal cycloalkyl of from 3 to 8 carbon atoms optionally substituted with 1 to 3 alkyl groups, L. when n is 0 an W- together with is a nitrogen heterocycle having 5 through 7 ring atoms, one of which is nitrogen and the remainder of which are carbon wherein X is oxo, then R' is not alkyl substituted with -C(0)NHOH-. ee M. when n is 0 and -C(H)p together with forms a fused ring S benzolactam in with the lactam nitrogen is substituted with an optionally substituted phenyl, biphenyl, phenylalkylene or biphenylalkylene substituent, and T is a bond then R' is not aminoalkylene or substituted aminoalkylene. N. W together with does not form a substituted or unsubstituted azetidinone. 798A 58. The compound according to Claim 57 wherein RI is aryl or heteroaryl. 59 The compound according to Claim 58 .vherein RI is selected from the group consisting-of phenyl, a substituted phenyl group of the formula: Rb' Rc 799 wherein R' is selected from the group consisting of acyl, alkyl. alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, and wherein Rb and Rc are fused to form a heteroaryl or heterocyclic ring with the phenyl ring wherein the heteroaryl or heterocyclic ring contains from 3 to 8 atoms of which from 1 to 3 are heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur Rb and Rb' are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy, and thioalkoxy with the proviso that when RC is hydrogen, then Rb and Rb' are either both hydrogen or both substituents other than hydrogen, 2-naphthyl, 2-naphthyl substituted at the 4, 5, 6, 7 and/or 8 positions with 1 to substituents selected from the group consisting alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, thioalkoxy, aryl, and heteroaryl, heteroaryl, and substituted heteroaryl containing 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl, thioalkoxy, thioaryloxy provided that said substiruents are not ortho to the heteroaryl attachment to the -NH group. i 60. The compound according to Claim 57 wherein R' is selected from the group consisting of mono-, di- and tri-substituted phenyl groups. 61. The compound according to Claim 60 wherein R' is a disubstituted 25 phenyl selected from the group consisting of 3 ,5-dichlorophenyl, difluorophenyl, 3,5-di(trifluoromethyl)-phenyl, 3, 4 -dichlorophenyl, 3,4- difluorophenyl, 3 -(trifluoromethyl)-4-chlorophenyl, 3 -chloro-4-cyanophenyl, 3- chloro-4-iodophenyl, and 3, 4 -methylenedioxyphenyl. 6 2 The compound according to Claim 60 wherein R' is a t o substituted phenyl selected from the group consisting of 800 4-azidophenyl, 4 -bromophenyl, 4-chiorophenyl, 4 -cyanophenyl, 4-ethy Iphenvi, 4-fluorophenyl, 4 -iodophenyl, 4-(pheny lcarbonyl)-phenvl. and 1- ethoxy)ethylphenyl. 63. The compound according to Claim 60 wherein R' is a trisubstituted phenyl selected from the group consisting of 3 4 ,5-trifluorophenvl and 3,4,5- trichiorophenyl. 64.. The compound according to Claim 57 wherein RI is selected from 2-naphthyl, quinolin-3-yl, 2-methylquinolin-6-yl, benzothiazol-6&yl, and phenyl. 15 65. The compound according to Claim 57 wherein RI is selected from the group consisting of phenyl, 1 -naphthyl, 2-naphthyl, :2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2 -hydroxyphenyl, 2-nitrophenyl, 2 -methylphenyl, 2-methoxypheny 1, 2 -phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl, 4 -chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4 -methylphenyl, 4 -hydroxyphenyl, 4 -methoxypheny 1, o. :4-ethoxyphenyl, 4-butoxyphenyl, 4 -iso-propylphenyl, 4 -phenoxyphenyl, 4 -trifluoromethylphenyl, 4 -hydroxymethylphenyl, 3 -methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3 -fluorophenyl, 3 -chlorophenyl, 000. 3-bromophenyl, 3-phenoxyphenyl, 3 -thiomethoxypheny 1, 3-methylphenyl, 25 3-trifluoromethylphenyl, 2 ,3-dichlorophenyl, 2, 3-difluorophenyl, 2,4- dichlorophenyl, 2 ,S-dimethoxyphenyl, 3 4 -dichlorophenyl, 3 4 -difluorophenyl, 3, 4-methylenedioxyphenyl, 3, 4 -dimethoxyphenyl, 3, 3 ,5-dichloropheny], 3 .S-di-(trifluoromethyl)phenyl, 3, S-dimethoxyphenyl, 2 ,4-dichlorophenyl, 2 ,4-difluorophenyi, 2, 6 -difluorophenyl, 3,4,5- trifluorophenyl, 3 4 ,-trimethoxyphenyI, 3,4 ,S-tri-(trifluoromethyI)phenyl, r, S P-q46-trifluorophenyl, 2 4 ,6-trimethylphenyl. 2,4, 6 -tri-(trifluoromethyl)phenyl, 2,3 .5-trifluorophenyl. 2,4 ,5-trifluorophenyl. 2, 5-difluorophenvl, 2-fluoro-3- trifluoron-ethylphenyl, 4 -fluoro- 2 -trifluoromethylphenyl, 2 -fluoro-4- trifluoromethiyiphenyl, 4-benzyloxyphenyl, 2 -chloro-6-fluorophenvil 2-fluoro-6- chlorophenyl, 2,3,4,5 6 -pentafluorophenyl, 2. 4-phenylphenyl, 2 -fluoro- 3 -trifluoromethylphenyl, adainantyl, benzyl, 2-phenylethyl, 3 -phenyl-n-propyl, 4 -phenyl-n-butyl. methyl, ethyl, n-propyl, iso-propyl. iso-butyl, sec-butyl, teri-buty 1, n-penty I, iso-valeryl, n-hexy I, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopent-l1-enyl, cyclopent-2- enyl, cyclohex-1-enyl, -CH,-cycilopropyl, -CI-1-cyclobutyl, -CH,-cyclohexyl, -CH,-cyclopentyl, -CH 2 CH-1-cyclopropyl, -CHCH- 2 -cyclobutyl, -CHCH 2 -cyclohexyl, -CH2CH2-cyclopentyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls, chioropyridyls, thien-2-yl, thien-3-yl, benzothiazol-4-yl, 2-pheny lbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphthen-2-y 1, thionaphtlien-3-yl, thionaphthen-4-yl, 2 -chlorothiophen5yl, 3-methylisoxazol-s yl, 2 -(thiophenyl)thien-5-yl, 6 -methoxythionaphthen2yl, 3-phenvl-1,2,4- 2 -phenyloxazol-4-yl, indol-3-yl, 1 -phenyl-tetraol-5-yl, allyl, 2-ccoexlehl (CH 3 2 CH =CHCHCH 2 CH(CH 3 OC(O)CH 2 thien-2-yl- methyl, 2 -(thien-2-yl)ethyl, 3 -(thien-2-yl)-n-propyl, 2 4 -nitrophenyl)ethyl, 2 4 -methoxyphenyl)ethyl, norboran-2-yi, 4 -methoxyphenyl)methyl, 2 -methoxyphenyl)methyl, 3 -methoxyphenyl)methy 1. 3 -hydroxypheny l)methyl, 4 -hydroxyphenyl)methyl, 4 -methoxyphenyl )methyl, 4 -methylphenyl)methyl, 4 -fluorophenyl)methyl, 4 -fluorophenoxy)methyl, 4 -dichlorophenoxy)ethyl, 4 -chlorophenyl)methyl, 2 -chlorophenyl)methyl, (1 -phenyl)ethyl, (1 -(p-chlorophenyl)ethyl, (1 -trifluoromethyl)ethyl, 4 -methoxyphenyl)ethyl, CH 3 OC(O)CH 2 benzyithiomethyl, 3 -(methoxycarbonyl)-n-propyl, indan-2-yi, 2 -methylbenzofuran-3yi), methoxymethyl, CH 3 CH=CH-, CH 3 CI- 2 CH 4 -chlorophenyl)C(o)CH,- (4-fluorophenyl)C(O)C2- 4 -methoxyphenyl)C(o)CH,, 4 -(fluorophenyl)- NHC(O)CW,-, 1 -phenyl-n-butyl, (042CHNHC(O)CH,CH, (CH 3 2 NC(O)CH,-, (q5) 2 CHNHC(O)CH,CH,-. methylcar bonylmethyl. 802 (2,4-dimethylphenyl)C(O)CH,- 4 -methoxyphenyl-C(O)CH,- phenvl-C(O)CH 2 CH 3 ethenyl, methyithiomethyl. (CH- 3 3 CNHC(O)CH, 4-fluorophenyl-C(O)CH,-, diphenylmethyl, phenoxymethyl, 3 4 -methylenedioxyphenyl-CH,-, benzo[b] thiophen-3-yl, (CH 3 3 COC(O)NHCHI, rans-styryi, H.,NC(O)CH,CH,-, 2 -trifluoromethylphenyl.C(O)CH 1 C(O)NHCH(O)CH,-, mesityl, CH 3 CH( =NHOH)CH,-, 4-CH 3 -0- NHC(O)CH,CH,-, OC(O)CH(O)CH,-, (CH 3 )2CHC(O)NHCH(4))- CH 3 CH:OCH 2 CH 3 OC(O)CH(CH 3 )(CH 2 3 2,2 ,2-trifluoroethyl, 1 -(trifluoromethyl)ethyl, 2-CH 3 -benzofuran-3-yl, 2-(2 4 -dichlorophenoxy)ethv 1, 4)SO,CH 2 3 -cyclohexyl-n-propyl, CF 3 CH 2 and N-pyrrolidinyl. 66. The compound according to Claim 5'7 where n is one or two, and each R 2 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic. 67. The compound according to Claim 57 wherein R2 is selected from :the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, teri-butyl, -CHCH(CH,CH 3 2 2-methyl-n..buryl. 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3 -methylpentyl, -CH,-cyclopropyi, -CH,-cvclohexyl, -CH,CH.,- :cyclopropyl, -CHCH 2 -cyclohexyl, -CH,-indol-3-yl, p-(phenyl)phenyl, o -fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p- *methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxvbenzy], p nitrobenzyl, m-trifluoromethylphenyl, p-(CH 3 )2NCH 2 CH 2 CH0benzyl p-(CH 3 3 COC(O)CH.,O-benzyl, p-(HOOCCH 2 O)-benzyl 2 -aminopyrid-6-yl, p-(N-morpholino-CH2CH2O).benyl -CH 2 CH,C(O)NH,, -CH,-imidazol-4-yl, -CH,-(3-tetrahydrofuranyl), -CH 1 -thiophen-2-yl, -CH(1 -methyl)cyclopropyl, -CH,-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, -CH,-C(O)O-t-butyl, -CH 2 -C(CH 3 3 -CH 2 CH(C{ 2 C- 3 2 -methylcyclopentyl, cyclohex-2-enyl, -CH[CH(CH 3 )2JCOOCH 3 -CHCHN(CH 3 -CH 2 C(CH 3 =CH 2 803 -CH,CH=CHCH 3 (cis and trans), -CHOH, -CH(OH)CH 3 -CH(O-t-butyI)CH,, -CH,OCH 3 -(CH 2 ,),NH-Boc, -CH,-pyridyl, pyridyl, -CH2-naphthyl, -CH,-(N-morpholino), p-(N-morpholiflo-CH,CH,O)-benzyl, benzo[b~thiophen-2-yl. 5-chlorobenzo[b]thiopheri2-yl, 4,5,6,7- tetrahydrobenzo[btiophen2yl, benzofb]thiophen-3-yl, chlorobenzo[bthiophen3yl, benzo[b] thiophen-5 -yl, 6-methoxvnaphth-2-yl -CHCH,SCHi 3 thien-2-yl, thien-3-yl. 68. The compound according to Claim 57 wherein the cyclic groups detined by W and is selected from 'the group consisting of lactones, lactams, thiolactones, thiolactams, heterocyclic and cycloalky] groups. 069. The compound according to Claim 68 wherein the cyclic group o o defined by W and forms a lactarn or thiolactam ring of the 0 15 formula: T I 00 0.* .0.0. 0.0 i 804 -C(H)P 111 T N C wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R 2 and -ZR" 1 where Z is a substituent selected from the group consisting of and NR 2 0 each R 2 0 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R" 1 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the 25 proviso that when Z is or any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3. W- ;i^ 805 The compound according to Claim 68 wherein the cyclic group defined by WA together with is selected from the group consisting of: Mt) (Ra)w 0 gN M 0 Rb (Ra)w (Ra)w N 0 Rb ,(Ra)w a a a. a. a a N Rb ,Mt b 806 NN 0 \b 0 Rb0 Rb (V) N 0 Rb 0 Rb I (Ra), (R) N N 0 Rb 0 ~Rb .:Rb 25 M N, 0 N R b7 ND 807 Rb Re N (V N (V)t A N N N Re O Rb S wherein A-B is selected from the group consisting of alkylene, alkenylene, 15 substituted alkylene, substituted alkenylene and Q' is oxygen or sulfur; each V is independently selected from the group consisting of hydroxy, Sacyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like; RI is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; Rb is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, heteroaryl, heterocyclic, and the like; 25 Rc is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl, and substituted cycloalkyl; t is an integer from 0 to 4; t' is an integer from 0 to 3; and w is an integer from 0 to 3. .36 71. The compound according to Claim 68 wherein the cyclic group efined by W, together with is a ring of the formula: 808 C(H) I OH OH or T -C(H)p S 20 CH *SH SH S wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(Rt2Z)qR2,- and -ZR2- where Z is a substituent selected from the group consisting of and S NR 20 each R 2 0 is independently selected from the group consisting of alkyl, Salkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 2 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is or any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the or and q is an, integer of from 1 to 3. 72. The compound according to Claim 71 wherein the alcohol or thiol substituted groups is selected from the group consisting of 809 (Ra)w (Ra)w OH OH Mt) MV) HO (Ra)w OH OH wherein each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, too. substituted alkenil alkynyl substituted alkynl'1 m ino, a i o c l Ilkarl .0.4 :lamnaylar 1 aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, 20 thioalkoxy, substituted thioalkoxy, trihalomethyl and the like; R' is selected .from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; I is an integer from 0 to 4; and w is an integer from 0 to 3. 810 73. The compound according to Claim 68 wherein the cyclic group defiped by W, together with forms a ring of the formula: T C O wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, and -ZR 2 where Z is a substituent selected from the group consisting of and NR 20 each R 2 0 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R' is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is or any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the or and q is 25 an integer of from 1 to 3. 74. The compound according to Claim 8 wherein the cyclic group defined by W, together with forms a ring of the formula: -C(H)p C 0 R< II o0 811 wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R 21 Z)QR 2 1 and -ZR 1 where Z is a substituent selected from the group consisting of and NR 2 each R" is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 2 1 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is or any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3. The compound according to Claim 74 wherein the compound of formula I is selected from the group consisting of *5M S*O* (Ra) (Ra) 2o C 0 6 0006 wherein each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, stituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, 812 aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like; R" is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; t is an integer from 0 to 4; and w is an integer from 0 to 3. 76. The compound according to Claim 68 wherein the cyclic group defined by W, together with forms a ring of the formula: -CH)p C S o wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, 2 1 and -ZR 1 where Z is a substituent selected from the group consisting of and NR 20 each R 2 0 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 2 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the 30 proviso that when Z is or any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3. 77. The compound according to Claim 68 wherein the cyclic group by W, together with forms a ring of the formula: 813 T -C(H)p II S wherein p is zero or one, T is selected from the group consisting of alkvlene, substituted alkylene, alkenylene, substituted alkenylene, -(R 2 and -ZR where Z is a substituent selected from the group consisting of and NR each R" is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl. 20 substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 2 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is or any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3. 78. The compound according to Claim 68 wherein the cyclic group defined by W, together with forms a ring of the formula: S. T -C(H)p S RZ sff s.I 814 wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R 2 Z)qR, and -ZR 2 where Z is a substituent selected from the group consisting of and NR 20 each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 2 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is or any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3. 79. The compound according to Claim 68 wherein the cyclic group defined by W, together with forms a ring of the formula: wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R 2 Z)qRl 2 and -ZR 1 30 where Z is a substituent selected from the group consisting of and NR 2 0 each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyi, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 2 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is or any unsaturation in the alkenylene and 815 substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3. The compound according to Claim 78 wherein the compound of formula I is selected from the group consisting of: ,(Ra)w V) t (Ra)w i; t(V) (Ra0 O 81. The compound according to Claim 6 8 wherein the cyclic group defined by W, together with forms a ring of the formula: 816 -C(H)p C S wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, and -ZR 2 where Z is a substituent selected from the group consisting of and NR 2 0 each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 2 is independently "alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is or any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3. S* 82. The compound according to Claim 68 wherein the cyclic group defined by W, together with forms a ring of the formula: 817 T -C(H)p CH I SH wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R 2 and -ZR 2 where Z is a substituent selected from the group consisting of and NR 2 0 each R 2 0 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl. 20 substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 2 is independently *alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is or any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3. 83. The compound according to Claim 68 wherein the cyclic group defined by W, together with forms a ring of the formula: T -C(H)p CH NR 2 0R 2 0 818 wherein p is zero or one, T is selected from the group consisting of alkylene, substituted alkylene, alkenylene. substituted alkenylene, -(R 21 Z)qR, 1 and -ZR 21 where Z is a substituent selected from the group consisting of and NR 20 each R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is or any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the or and q is an integer of from 1 to 3. 84. A compound selected from the group consisting of: 1 -(3,5-iloohnlctl -laiy)aioiezsbrn 1 1 dfurpeyaey)Lalnnl-mn--R-nao 1 2-(N S-difluorophenylacetyl)4L-alaninyl)-amiino- I -cyclohexanol 1 ,5-difluorophenylacetyl>L-alaninyl)-amino- 1,2,3,4- tetrahydro-2-naphthol S-difluorophenylacetyl)-L-alaninyl)-aminobenz[fl cycloheptan-2-ol. S-difluorophenyacety)-L.alaniny] amino- 7-dihydro-6H- dibenzo[a,c]cyclohepten-6-ol I '-(3,5dfurpeyactl -lnnl)aiona--n 2-(N '-(phenylacety l)-L-alaninyl)aminocyclohexan- 1-one ,-difluorophenylacetyl)-L-aaninyl] amino- 7-dihydro-6H- dibenzo[a ,clcyclohepten-6-one 3-(N S-difluorophenylacetyl)-Lalaninyl)amino-y-butyrolactone 4 -dichlorophenyl)-L-alaniny I)amino--y-butyrolactone 819 4-(N '-(cyclopenrylacetyl)-L-alaninyl)amino-1, 1-dimethyl-3-isochromanone 4-(N ,S-difluorophenylacety)-L-alaniny1)amino-.1, 1-dimethyl-3- isochromanone 3-(N '-(3,5-iloohnlctl -laiy~mn-ybtrlca 3-(N '-(3,5-iloohnlcey)Laaiy~mio6vlrlca 1 -benzyl-3-(S)-(N S-difluorophenylacety)Laaniny)aino-fl 0 valerolactrm 3-N' -(3,5-iloohnlc l)Laaiy~rio4-ehlc-arlca 3-(N S-difluorophenylacetyl)-L-alaninyl)amino- 1,2,3,4- tetrahydroquinolin-2-one 1 -benzyl-3-(N ,-difluorophenylacetyl)>L-alan.l)amino- 1,2,3,4- tetrahydroquinolin-2-one :0.00. 4-(N S-difluorophenyacey)-L-alaninyl)amji 0 1,2,3,4- tetrahydroisoquinolin-3.-one 4-(N S-difluorophenylacetyl)-Lalaninyl)amino.2..nzyl.1,2,3,4- tetrahydroisoquinolin-3-one 4-(N ,S-difluorophenylacety1)-L-alaninyl)amino-l1-methyl- 1,2,3,4- tetrahydroisoquinolin-3-one 4-(N S-difluorophenylacey)-L-alaninyl)amino. 1-phenyl- 1,2,3,4- tetrahydroisoquinolin-3 -one 4-(N S-difluorophenylacety I)-L-alaninyI)amino-6-fluoro-1,2,3,4- tetrahydroisoquinolin-3-one 4-(N '-(3,5-ilooheyaey)L-lnnla n--loo1,2,3,4- tetrahydroisoquinolin-3-one 4-(N ,S-difluorophenylacetyl)-L-alaninyl)amino-2phenethyl- 1,2,3,4- tetrahydroisoquinolin-3-one 4-(N ,S-difluorophenylacetyl)4L-alaninyl)amno2methyl 1,2,3,4- tetrahydroisoquinolin-3 -one ,-difluorophenylacetyl)Lalaninyl)amino6phenyl 1,2,3,4- eraydroisoquinolin3-one 820 4-(N .5-difluorophenyacetyLaaniny)mino-7pheny- 1.2,3,4- tetrahydroisoquinol in-3-one S-difluorophenylacetylyL-alaninyl)..(9-aminofluroren-1 -yl)glycine 6- lactam 3-(N '-(phenylacetyl)-L-aaniny)aminoe-caprolactam '-(3,5dfurpeyaet lnnl-mioc-arlca .S-difluorophenylacetylyL-alaniny)amin 0 I-benzyI-e-- caprolactam .S-difluorophenylacetyyL-alaninyl)amin 0 1-(2-methoxyethyl)-e- caprolactarn .S-difluorophenylacetyl)-Lalaninyl)amino 1 -ethyl-e-caprolactam 20 3-N 3-N' S-difluorophenylacety)Lalaniny)amjn-5 -ethyl-c--caprolactam dfurpeyaey)Laaiylaio--ezlc-arlca .S-difluorophenyacety)-Laanijnyl)aminl 0 .I-benzyl-4 ,7- methano-c--caprolactam '-(cyclopentylacetyl)-L-alaniny)mino 1-benzyl-e-caprolactam V. '-(cyclopentylacetyl)-L-pheny lglycinyl)amino- 1 -benzyl-e- caprolactain -(3,5S-difluorophenylacetyl)-L-alaninyl)amino 1l-(2-phenethyl)-f- caprolactam '-(cyclopentylacetyl)Lphenylglyciny)amino 1 -(2pethyl-e caprolactam 3-(N ,4-dilorophenyl)-D )L-alaniny)amino-8cta actam PSIoaca 45-w3( -3~~i~oohn~cey)~~my)iootnl 821 4-(N .S-difluorophenylacet )-L-alarinyl)amino7benzyl 1,2,3,4- tetrahydroisoquinolin-3-one 4-(N ,$-difluorophenylacetyl)-L-alaninyl)amnj 0 1 -benzyl- 1,2,3,4- tetrahydroisoquinolin-3-one 4-(N 5-difluorophenylacetyl )-L-alaniny)amino-2-meth.yI1 -pheny I 1,2,3 ,4-tetrahydroisoquinol in-3-one 4-(N .5-difluoropheny lacety l)-L-alaniny ])amino- 1 (pyrid-2-yI)- 1, 2,3,4- tetrahydroisoquinol in-3 -one 4-(N .S-difluorophenylacetyl)-L-alainy)amino- 1 -(pyrid-3-yI)- 1,2,3,4- tetrahydroisoquinol in-3 -one 4-(N .5-difluorophenylacetyl)-Lalanny)mino 1 -(pyrid-4-yI)- 1, 2,3,4- tetrahydroisoquinol in-3 -one 3-[N .S-difluorophenylacetyl)>L-alaninyl] -amino-i1 -methyl-2-indolinone *3 3-[N ,5-difluorophenylacetyl)-L-alainyl) amino- 1 -methyl-4-phenyl-3 ,4- trans-dihydrocarbostyril 3- .S-difluorophenylacetyl)-L-alaninylI amino- 1 -methyl-4-phenyl-3 ,4- cis-dihydrocarbostyril 3-[N S-difluorophenylacetyl)-L-alanmnyl] amino-4-phenyl-3 ,4-trans- dihydrocarbostyril 1 -(N'-(3,5dfurpeyactl--lnnl mn--ehl1,3,4,5- retrahydro-2H-3-benzazepin-2-one 1 -SdifluorophenylacetylyL-aaninyl)amino3 -ethyl 4 '-fluoro- 1,3 4 ,5-tetrahydro-2H-3-benzazepin-2-one ,5-difluorophenylacetyl)amino. 1 -ethyl 5-dimethyl- 1, 3, 4,5- tetrahydro- 2-1-benzazepin-2-one 3-(N ,5-difluorophenylacetyl)-L-alapnjnyl)amino- 1, 3,4, 5-tetrahydro-2H- 1 benzazepin-2-one 3-(N ,5-difluoropheny lacetyl)-L-alaniny1) amino- 1 -benzyl- 1, 3,4,5- tetrahydro-2H-3-benzazepin-2-one (cyclopenty lacetylI)amino- I1-ethyl -5,5 -dimethyl1- 1, 3,4, 5-tetrahydro-2H __-benzazepin-2-one 822 .S-difluorophenylaceyl)-L-alaninyI)amino- 1 -methyl- 1, 3,4,5- tetrahydro-2H-- 1 -benzazepin-2-one .5-difluorophenylaceryl)-L-aaniny)mino- 1, 5-dimethyl- 1, 3,4,5- tetrahydro-2H- 1 -benzazepin-2-one 3-(3 ,5-difluorophenylacetyl)amino. 1, 5-dimethyl- 1, 3,4 ,5-tetrahydro-2- I 1- benzazepin-2-one .S-difluorophenylacety)-L-aaninyl)mino- 1 -methyl 1, 3,4 .5-tetrahydro-2H- 1 -benzazepin-2-one ,5-difluorophenylaceryl)-L-aaliny)mino- 1 -ethyl 1, 3,4, 5-tetrahydro-2H- 1 -benzazepin-2-one S-difluorophenylacetyl) -L-alaninyl)amino- I -methy 1, 3,4, 5-tetrahydro-2H- 1 -benzazepin-2-one ,5-difluorophenylacetyl)-L..alaninyl }-amino-3 ,3-dimethyl-5 ,7- 20 dihydro-6H-benz[b]azepin-6-one N ,5-difluorophenylacetyl)-L-alaniny 1) amino- 3,3 ,7-trimethyl1-5,7 7- dihydro-6H-benzb] azepin-6-one 5-{N ,-difluoromandelyl]-L-alaninyl}amino-3 3, 7-trimethyl-5 ,7- dihydro-6H-benz[b]azepin-6-one 1 ,S-difluorophenylacetyl)-Laainy)amino5pheny..1,3,4,5- tetrahydro-2H-!3-benzazepin-2-one ,5-difluorophenylacetyl)-L-alaninyl)amino- 1 -ethyl-S 3 4 ,5-tetrahydro-2H- I-benzzepin-2one S-difluorophenylacetyl)-L-alaninyl] amino-7 -methy 1-5,7- *35 dihydro-6H-dibenz[b,d]azepin-6-one and alaninyl) amino-7-methyl-5 ,7-dihydro-6H-dibenz jb dJazepin-6-one '-(3,5dfurpeylc-eocrl)Laaiy mio7mt-, 7- dihydro-6H-dibenz[b ,dl azepin-6-one ,S-difluorophenylacetyl)-L-vainy]amino7-mthyps 7-dihydro- 6H-dibenz d]azepin-6-one ~5 ,-difluorophenyaceryl)Lterr-leucinylamino7methyl.s,7- d ihydro-6H-dibenz[b azepin-6-one 823 5-(S)-[N'-((S)-3,5dfurpey-ehdoyaey)Lvlnlaio7 methyl-S. 7-dihydro-6H-dibenz[b d] azepin-6-one ,-difluorophenyl-c-hydroxyacetyl)-L.tert-leucinylIamino-7 methyl- 7-dihydro-6H-dibenz[b azepin-6-one '-(3,5dfurpeyaetl--lnnlaio--mtoyc 7- dihydro-6H-dibenzb,d]azepin-6-one 5 -(3.-iloohnlct)Laai ny1 mn--(etycroylt) 7 -dihydro-6H-dibenz[bdlazepin..6-one ,-difluorophenyacety)-Laaniny]mino7(3 ,3-dimethyl-2- ,7-dihydro-6H-dibenz[b azepin-6-one dfurpeyaey)Laainlaio7(opoiyaey) 7-dihydro-6H-dibenz[b .dlazepin-6-one 2 -Hydroxy- 3 -methybutyry)L.aaniny)mino7metyl 5, 7-dihydro-6H-dibenz[b,d] azepin-6-one -cyclopentyl-ce-hydroxyacetyl).L-valinyl] amino-7-methyl-5 ,7-dihydro- 6H-dibenz~b, dlazepin-6-one and 3 -dimethyl-2-hydroxybutyryl>L..alaninyl)amin-7- methyl-S ,7-dihydro-6H-dibenz[b ,d]azepin-6-one -cyclopentyl-c-hydroxyacetyl)L-ert-leucinyl] amino-7-methyl-5 ,7- dihydro-6H-diberiz[b ,d]azepin-6-one 5- -cyclopentyl-ca-hydroxyacetyl)-Lalaninyl] axino-7-methyl-5 ,7-dihydro- 6H--dibenz[b ,d]azepin-6-one ,-difluorophenylacetyl)-L-alaninyi]amino-5 7-dihydro-6H, 7H- 35 dibenz[b,d]azepin-6-one ,-difluorophenylacetyl)-L-alannyl] amino-7-(2-methylpropyl)-5,3- dihydro-6H-dibenb ,d]azepin-6-one 5-[N '-(-yrx--mtybtrl)Lvlnlamn--el5 ,7-dihydro- 6H-dibenz[b ,dlazepin-6-one and R)-2-hydroxy -d imethybuyrl)-Lvainy 1)amnino-7 methyl- 7 -dihydro-6H-dibenzb azepin-6-one 5- {N 4 -phenyl-furazan-3-yl)aianinyI }-amino-7-methyl-5 ,7-dihydro-6H- N ibenz[b~dlazepin-6-one 824 S-difluorophenylacetyl)-L-alaninyl} amino-7-methyv. 1 ,2,3,4,5.7- hexahydro-6H-dicyclohexyl d)azepin-6-one S-difluorophenylacety1)- L-alaniny 1) amino- 7-phenbuty[.-5 ,7-dihyd ro- 6H-dibenzfb,dlazepin-6-one .S-difluorophenylacetyl)-L-alaninyl }amino-7-cyclopropymethyls 7- dihydro-611-dibenb d]azepin-6-one 5-{N ,S-difluorophenylacety!)-L-alaninylamino-7(2' ,7-dihydro-H-dibenz[b azepin-6-one ,-difluorophenylacetyl) alaniny! 1)amino- 7-cyc lohexyl-5, 7- dihydro-6H-dibenzb, dlazepin-6-one ,S-difluoromandely1]-L-alaniny1 }amino-9-fluoro-7-methyl-5.7- dihydro-6H-dibenz~b dlazepin-6-one {N .S-difluoromandelyll-L-alaniny) }-amino- 1 3 -fluoro-7-methyl-5 ,7- dihydro-6H-dibenzb,dlazepin..6 0 ne N ,S-difluoromandely] -L-alaniny) }amino-1 IO-fluoro-7-methyl-5, 7- dihydro-6H-dibenz[b ,diazepin-6-one 5-{N .S-difluoromandelylL-alaninyl}amino-7.cyclopropylmethyl. 7 -dihydro-6H-dibenz[b,d]azepin6one 5-{N'-[(S)-3,5dfurmneyl--lnnlain--hnuy ,7- dihydro-6H-dibenz[b dazepin-6-one 5 '-[()35dfuooadli-Lvlnlanio7ccoroymty ,7 dihydro-6H-dibenzlb ,dljazepin-6-one {N ,S-difluoromandelyl]-L-valinyl} amino-7-phenbutyl-5 ,7-dihydro- 35 6H-dibenzflb,d]azepin-6-one .S-difluoromandely]-L-valiny1 }ainino-7-hexyl- 7-dihydro-6-- dibenb ,d]azepin-6-one ,S-difluoromandely]-L-valiny1 amino- lO-fluoro-7-methyl-5 ,7- dihydro-6H-dibeTnz[b ,d]azepin-6-one .S-difluoromande lyl] -Lval iny 1) amino-i 1 3 -fluoro-7-methy1-5 ,7 dihydro-6H-dibenz[b ,dlazepin-6-one 3, difluoromandely 1] -Lva iny 1) amino- 9 fluoro-7 -methy1-5 ,7 7- hydro-6H-diberzb,d]azepin-6-one 825 3-(N 4 -methylenedioxyphenylacetylyL-alaninyl)amino-2 ,3-dihydro- I1- 1 H-1, 4 -benzodiazepin-2-one 3-(N 2 -methoxyphenoxyacetyl).L-alaninyl)amino-2 ,3-dihydro- 1 -methyl phenyl- 1 H-i 1.4-benzodiazepin-2 -one 3-(N 4 -isopropylphenoxyacety)L-aanny)mino-2,3-dihydro- 1 phenyl- 1 H-i ,4-benzodiazepin-2-one 3-(N '-(ethoxyacetyl)-L-alannyl)amino-2,3-dihydro- I -methyl-5-phenyl- 1 H- 1 ,4-berizodiazepin-2-one 3-(N 4 -phenoxyphenylacety)-L-alaninyl)mino2 -,3-dihydro- 1 -methyl-S phenyl-1H- 1,4-benzodiazepin-2-one 3-(N 4 -ethoxyphenyacetyl)Laanny)aino-2 3-dihydro- 1 -methyl phenyl- 1H- 1 4 -benzodiazepin-2-one S-dimnethoxyphenylacetyl)-L-alaninyl)amino-2.3-dihydro- 1 -methyl- 5-phenyl- 1 H-i ,4-benzodiazepin-2-one ,5-difluorobenzoyl)-L-alaninyl)amino.2,3-dihydro- 1 phenyl- iH- 1,4-benzodiazepin-2-one 3-(N '-(o-tolylacetyl)-L-alaninyl)amino-2 ,3-dihydro-l1-methyl-5-phenyl- 1H- 1 ,4-benzodiazepin-2-one 3-(N 3 -diphenylpropionyl)-L-alaninyl)amino-2, 3-dihydro-l1-methyl-5- phenyl- 1H-1 4 -benizodiazepin-2-one 3 -phenoxypropiony)-L-aaniny)mino-2, 3-dihydro- 1 phenyl- 1H- 1,4-benzodiazepin-2-one '-(indole-3-acetyl)-L-alaninyl)amino.2 ,3-dihydro-l1-methyl-5-phenyl- 1H- 1 ,4-benzodiazepin-2-one 3-(N 4 -(trifluoromethyl)phenylacetyl)>L.alaninyl)min-2 3-dihydro- 1 1 H-i 4 -benzodiazepin-2-;one 3-(N 4 -methylphenoxy)acetyl)-L-alaninyl)amin-2 3-dihydro- 1 phenyl- 1 H- 1,4-benzodiazepin-2-one 3-(N 4 -(hydroxymethyl)phenoxyacetyly.L-alaninyl)amino.2 3-dihydro- 1 1 H-i 4 -benzodiazepin-2-one 3(N' 2 -phenoxyphenylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 phenyl- IH- 1,4-benzodiazepin-2-one 826 3-(N 3 -phenoxyphenylacey)-L-alaniny1)amino.',,3-dihydro- 1 phenyl- 1 H-i 1, 4 -benzodiazepin-2-one 3-(N 4 -dich orophenoxyacetyl)-L-alaninyI)amino-2,3-dihydro- 1 -methyl- 5-phenyl- I1H-1 ,4-benzodiazepin-2-one 4 -fluorophenoxyacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 phenyl- 1H- 1 4 -benzodiazepin-2-one 3-(N '-(methylthio)acetyl)-L-alaniny)mino-2,3-dihydro- 1 -met hyl-5-pheny 1- IH- 1 ,4-benzodiazepin-2-one 3-(N '-(methoxyacetyl)-L-alaninyl)amino-2 ,3-dihydro- I -methyl-5-phenyl -il- 1, 4-benzodiazepin-2 -one '-(phenoxyacetyl)-L-alaninyl)amino-.3-dihydro- 1 -methyl 1H- 1 4 -benzodiazepin-2-one '-(phenylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 -methyl-S -pheny I- 1 H-i1, 4 -benzodiazepin-2-one 2 -phenoxybutyryl)-L-alaninyl)amino-2 ,3-dihydro- 1-methyl-S phenyl 1iH- 1 4 -benzodiazepin-2-one 3 -methoxyphenoxyacetyl)-L-alaninyl)amno 0 2 3-dihydro- 1 1 H-i 1,4-benzodiazepin-2 -one 4 -(trifluoromethyl)phenylacetyl)glycinyl)-L-alaninyl)amino.2 ,3- dihydro- 1 -methyl-5-phenyl- 1 H-i ,4-benzodiazepin-2-one 4 -butoxyphenylacetyl)-L-alaniny)mino-2 .3-dihydro- 1 phenyl- 1 H-i ,4-benzodiazepin-2-one 3 2 -methoxyphenyl)propionyl)-L-alanAnyl)amino-2 ,3 -dihydro I1- methyl-5-phenyl-1H-1 ,4-benzodiazepin-2-one 4 -fluorophenylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 phenyl- iN- 1 ,4-benzodiazepin-2-one '-(isopropoxylacetyl)-L-alaninyl)amo-2 ,3-dihydro- 1 -methyl-S ph enyl- 1 H-1, 4-benzodiazepin-2-one 1 -phenyl- iH-tetrazole-5-acetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 1 H-1, 4-benzodiazepin-2-one 4 -methylenedioxyphenyl)propionyl)..L.alaniny)mino-2 ,3- r1~ "4 dihydro- 1 -methyl-5-phenyl- 1 H- 1, 4 -benzodiazepin-2-one 827 3 -cyclopentylpropionyl)-L-alaninyl)anmin-2 ,3-dihydro- 1 -methyl- 1H- 1.4-benzodiazepin-2-one '-(2-cyclopencene- 1 -aceryl)-L-alaninyl)amino-2 3-dihydro- 1 -methylI- 5-phenyl- 1 H-1, 4-benzodiazepin-2-one 2 -chloro-6-fluorophenylacetyl)-L-alaninyl)amino.2 3 -dihydro- 1 1 H-i 1,4-benzodiazepin-2 -one '-(cyclohexylacetyl)-L-alaninyl)amino-2,3-dihydro- 1 phenyl- 1 H-i ,4-benzodiazepin-2-one ,-difluorophenylacetyl)-L-alaninyI)amino-2,3-dihydro- 1 1 H-i ,4-benzodiazepin-2-one -(pentafluorophenoxyacetyl)-L-aaniny)mino-2 ,3-dihydro- 1 1H- 1,4-benzodiazepin-2-one -dimnethylphenoxyacety)-L-alaninyl)amino.2 3-dihydro- 1 methyl-5-phenyl- 1 H-i ,4-benzodiazepin-2-one 3 4 -chlorophenylacetyl)-L-alaninyI)amino..2,3.dhydro- phenyl- 1H-i ,4-benzodiazepin-2-one 3 -chlorophenoxyacetyl)-L-alaniinyl)amino.2 3-dihydro- 1 -methyl- 5-phenyl-1IH- 1 ,4-benzodiazepin-2-one '-(benzo[b]thiophene-3-acetyl)-L-alaninyl)amino-2,3 -dihydro- 1 1 H-i ,4-benzodiazepin-2-one '-(benzoylformyl)-L-alaninyl)amino-2 ,3-dihydro- 1 I H- 1 ,4-benzodiazepin-2-one ()S)-3-(N'-(3,5S-dimiethoxyphenylacety)-L-alaninyl)amino-2 ,3-dihydro- 1 methyl-5-phenyl-1H-1 ,4-benzodiazepin-2-one ,S-dimethylphenylacety1)-L-aianinyl)amino-2 ,3-dihydro- 1 rnethyl-5-phenyl-i1H-1, ,4-benzodiazepin-2 -one 2 6 -difluorophenylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 1 H-i 1,4-benzodiazep in-2 -one 2 4 -difluorophenylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 1H- 1,4-benzodiazepin-2-one j '-(mesitylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 1H-i .4-benzodiazepin-2-one 828 4 -biphenylacery1)-L-alaniny)amino_2 3-dihydro- 1 phenyl-1IH- 1, 4 -benzodiazepin-2 -one 4 -difluorophenylacetyI)-L-alaninyI)amino-2.3-dihydro- I1- methyl-5-phenyl-1IH- 1 4-benzodiazepin-2-one '-(trans-styrylacety1)-L-alaninyl)amjno-2, 3-dihydro- 1 phenyl- 1 H-1, 4 -benzodiazepin-2-one 3 -benzoylpropionyl)-L-aaniny)amino2,3di.ydro- I phenyl- 1 H-i 1, 4 -benzodiazepin-2 -one '-(trans-3-hexenoy)-L-alaniny1)amino-2 ,3-dihydro- 1 phenyl- I H-1, 4 -benzodiazepin-2-one '-(heptanoyl)-L-alaninyl)amino2,3-.dihydro. 1 -methyl-5-phenyl- 1 H- 1 .4-benzodiazepin-2-one 3 4 -mneth yiphenyI)propiony).Laaniny)mino-2 ,3-dihydro- 1 methyl-5-phenyl- 1 H-I 4 -benzodiazepin-2-one 3 4 -chlorophenyl)propionyl).L-alaninyl)amino.2 3-d ihydro- 1 1H- 1,4-benzodiazepin-2-one 3 -phenylbutyryl)-L-alaninyl)amino-2 ,3-dihydro- 1 phenyl- 1H- 1 .4-benzodiazepin-2-one 4 4 -methoxypheny)buy).L-alaniny)mino-2,3-dihydro- 1 1 H- 1,4-benzodiazepin-2-one 3 -methoxycarbonylpropiony)Lalafiny)mino- 2 3-dihydro- 1- -phenyl-l1H-i ,4-benzodiazepin-2-one 4 -phenylbutyry1)-L-alaninyl)amino-2 ,3-dihydro-l1-methyl-5- phenyl-1H-1 4 -benzodiazepin-2-one 3 -(benzylthio)propiony)-L-alaninyl)amino.2 ,3-dihydro- 1 -methyl- 1H- 1, 4 -benzodiazepin-2-one 3 -methylpentanoy)-L-alan~inyl)amino-2 3-dihydro- 1 phenyl- 1 H-i 4 -benzodiazepin-2-one '-(6-methoxycarbony lheptanoyl)-L-alaninyl)amino-2, 3-dihydro- 1 methyl-5-phenyl-1H- 1,4-benzodiazepin-2-one 2 -indanylacetylI)-L-alaninyl) amino-2 ,3 -dihydro- 1 Sphenyl- 1H- 1,4-benizod iazepin-2 -one 829 4 -methoxyphenylacetyl)-L-alaninyl )amino-2 ,3-dihydro- 1 -methyl- 5-phenyl-1IH-l 4 -benzodiazepin-2-one 2 -chlorophenoxyacetyl)-L-alaninyl )amino-2 ,3-dihydro- 1 -methyl- 5-pbenyl- 1H- 1,4-benzodiazepin-2-one '-(2-thiopheneacetyl )-L-alaninyl)amino-2 ,3-dihydro- 1 -methyl-S phenyl- 1 H-i 4 -benzodiazepin-2-one 3 3 -(tfifluoromethyl)phenylaceyl)-Lalaninyl)amino-2 ,3-dihydro- I1- 1H-i, 4-benzodiazepin-2-one 4 -tolylacetyl)-L-alaninyI)amino-2, 3-dihydro- 1 -methyl-5-pheny I- 1IH- 1 4-benzodiazepin-2-one 6 -difluoromandelyl)-L-alaninyl)amino-2 3-dihydro- I phenyl-I1H-1 ,4-benzodiazepin-2-one 4 -methoxyphenyl)propionyl)-Laainyl)mino-2, 3-dihydro- 1 methyl-5-phenyl- 1H- 1 ,4-benzodiazepin-2-one ,S-difluorophenylacetyl)-L-alaninyl)amino-2, 3-dihydro- 1 1 H- 1, 4-benzodiazepin-2 -one '-(m-tolylacetyl)-L-alaninyl)amino-2, 3-dihydro-l1-methyl-S -pheny I- 1H- 1, 4 -benzodiazepin-2-one 3 -fluorophenylacetyl)-L-alaniny)mino-2,3-dihydro- 1-methyl phenyl- 1H- 1,4-benzodiazepin-2-one 4 -chlorophenoxyacetyl)-L-alaiiinyl)amino-2 ,3-dihydro- 1 -methylI- *.5-phenyl- 1 H-1, ,4-benzodiazepin-2 -one 2 -naphthylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 phenylIH- 1,4-benzodiazepin-2-one 3 -chlorophenylacety1)-L-alaniny)amino2,3-dihydro-l1-methyl-S phenyl-1H- 1,4-benzodiazepin-2-one 3 -methylphenoxyacetyl)Lalaninyl)mino-2,3-dihydro- 1 -methyl- 1 H-i ,4-benzodiazepin-2-one .4-methy Ienedioxyphenylacetyl)-L-alaninyl)anQ2 3-dihydro- 1 -methyl-5-phenyl- 1 H-1, 4 -benzodiazepin-2-one eoyaey)/-laiy~aio2,-iydol meth 1--hnl-IH-14-ezdaei-- 831 4 -fluoromandelyl)-L-alaniny)amino-2 ,3-dihydro- 1 phenyl- 1H- 1, 4 -benzodiazepin-2-one 4 -thionaphthenacetyl)-L-alaniny)amin 0 .2 ,3-dihydro- 1 phenyl- IH-1 4 -benzodiazepin-2-one '-(methoxyacery)-L-alaninyl)anino-2 3 -dihydro- 1 lH- 1, 4 -benzodiazepin-2-one '-(ethoxyacetyl)-L-alaniny1)amino-2 ,3-dihydro- 1 11- 1, 4 -benzodiazepin-2 -one 3 -(N'-(3-indolepropionylyL-alaniny)azino.2,3-dihydro- 1 phenyl- 1H- 1, 4 -benzodiazepin-2-one (S--N-3(-horpey~rpoy) -l~~y~mn-,3-dihvdro- 1 1H- 1, 4 -benzodiazep in-2 -one (S)-3-(N'-(butyryI)-L-aanny)ino-2,3-dihydro- I -methyl-5-pheny]- I H- 1, 4 -benzodiazepin-2 -one '-(hexanoyl)-L-alaninyl)amino-2,3-dihydro- 1 -methyl-5-phenyl- 1 H- 1 4 -benzodiazepin-2-one '-(5-phenylpentanoyl)-L-alaninyl)amino.2 3-dihydro-l1-methyl-5- phenyl- 1H- 1, 4 -benzodiazepin-2-one 4 2 -thienyl)buyryl)-Laannyl)ino-2,3-dihydro-l1-methyl phenyl-l1H-i 4 -benzodiazepin-2-one 4 -nitrophenoxyacetyl)-L-alaniny I)amino-2, 3-dihydro- 1 -methyl1-S phenyl- I1H- 1, 4 -benizodiazepin-2 -one -(3-(3-mehoxypnefly)propiony)L.alaninyai)njf 0 2, 3-dihydro- 1 35 mehl5pey-H14-ezdaei--n -(5-methylhexanoy)-L-alaninyI)amlo.2 ,3-dihydro-l1-methyl-5- phenyl-l1H-i 4 -benzodiazepin-2-one '-(hydrocinnamyl)-L-alaninyl)amjfl 0 ,3-dihydro-l1-methyl-5-pheny 1- 1 H-i 4 -benzodiazepin-2-one '-(octanoyl)-L-alaninyl)amino-2,3-dihydro-l1-methy]-5-phenyl-l1H- 1 4 -benzodiazepin-2-one -5- 3 3 -hydroxyphenyl)propionyl>L-alalinl)aiino-2, 3-dihydro- 1- I H- 1, 4 -benzodiazepin..2-one 832 3 4 -hydroxyphenyJ)propionyI)-L-alaninyl)amino-2 3-dihydro- I1- methyl-5-phenyl-1IH- 1 4 -benzodiazepin-2-one .S-trifluorophenylacety!)-L-aaniny)amin 0 .2 ,3-dihydro- 1 methyl-5-phenyl- 1I -1 ,4-benzodiazepin-2-one '-(cyclopentylacety)-L-alaniny I)axnino-2 ,3-dihydro- I phenyl-lI-- 1 4 -benzodiazepin-21-one 3 -(trifluoromethyl)butyIy)-L-alarinyl)amino-2 ,3-dihydro- I- methyl-5-phenyl-1H- 1 4 -benzodiazepin-2-one 2 -methy-3-Benzofraacety-Lalaniny)mino-2, 3-dihydro- 1 1 H-i 4 -benzodiazepin-2-one '-(propionyl)-L-alaninyl)amino-2, 3-dihydro- I -methyl-5-phenyl- 1 H- 20 1, 4 -benzodiazepin-2 -one goes '-(cyclopropylacety1)-Laainy)min-2 ,3-dihydro-l1-methyl-5- phenyl- lH- 1, 4 -benzodiazepin-2-one 3 -methoxypropionyl)-L-alaninyI)amino-2 ,3-dihydro-l1-methyl-S phenyl-l1H-i 4 -benzodiazepin-2-one 3 -(N'-(5-(thienyI)pentanoyl)L-alanny)mino.2 ,3-dihydro-l1-methyl-5- phenyl-1H- 1, 4 -benzodiazepin-2-one 3 4 -fluorophenyl)propionyl)>L.alaninyl)amino-2 ,3-dihydro- 1 *~methyl-S-phenyl- 1H- 1, 4 -benzodiazepin-2-one 3 4 -fluorophenoxy)propionyl)..L-alaninyl)amino-2,3 -dihydro- 1- 35 methyl-5-phenyl-1H-1 4 -benzodiazepin-2-one *So. 00.0(S)-3-(N 2 -norbornaneacetyI)-L-alanny)mino-2 ,3-dihydro- 1 -methyl-5 phenyl- 1 H-i 4 -benzodiazepin-2-one 3 -difluoromandelyl)-L-alaninyl)amino-2,3-dihydro- phenyl- 1 H-i ,4-benzodiazepin-2-one 3 -pentenoy)-L-alaninyl)amino-2 3-dihydro- 1 IH- I 4 -benzodiazepin-2-one 4 -dichlorophenoxy)butyyl).L-alaniny I)amino-2.3-dihydro- I1- 1H-i 4 -benzodiazepin2 -one 833 (S)--(N-(2.-dihloopheoxycety)-Lalainylamio-23-dihydro- 1- methyl-5-phenyl-IH-1 4 -benzodiazepin-2-one 3 4 -ch orobenzoyl)propionyl)..Lalanny)mino-2 .3-dihvdro- 1- methyl-5-phenyl-1H-i 4 -benzodiazepin-2-one 2 -fluorophenylacetyl).L-alanmnyl)amino-2 .3-dihydro- 1 phenyl- 1H-1, 4 -benzodiazepin-2 -one 3 -(N'-(2-(4-cyanophenoxy)2-meth~yI propionyl)-L-alainyl)aino-2,3- dihydro-l1-methyl-5-phenyl-l1H-i 4 -benzodiazepin-2-one 2 -nitrophenylacety)-Laaniny)mino-2,3-dihydro-l1-methyl-S phenyl-l--i, 4 -benzodiazepin-2-one 4 -(hydroxymethy)phenoxyacetyLalaniny)mino-2, 3-dihydro- 1 -methyl-5-phenyl-l1H-i 4 -benzodiazepin-2-one 2 -fluoro- 3 -(trifluoromethyl)phenylacety)-L-aaniny1)amino- 2 3- dihydro- 1-methyl-5-phenyl- 1H-i 4 -benzodiazepin-2-one 6 -trifluorophenylacetyl)-Lalaninyl)amino-2 ,3-dihydro- 1 methyl-5-phenyl- 1H-i 4 -benzodiazepin-2-one 4 -fluoro- 2 -(trifluoromethyl)phenylacetyl>L-alaninyl)amino- 2 ,3- dihydro- 1 -methyl-5-pheny I- 1 H-i 1, 4 -benzodiazepin-2 -one 4 4 4 -trifluorobut yy)-L-alaninyl)ainino-2 3-dihydro-l1-merihyl-5- phenyl-i1H- 1, 4 -benzodiazep in-2 -one 2 -fluoro-4-(trifluoromethyl)phenyacety)Lalainyl1)amino-2,3- dihydro-l1-methyl-5-phenyl-l1H-i 4 -benzodiazepin-2-one 4 -bromophenylacetyl)-L-alaninyl)amino.2 ,3-dihydro- 1 -methyl-S 35 phenyl- 1H-i 4 -benzodiazepin-2-one 3 4 -fluorobenzoyl)propionyl)..L-ainyl)amino-2, 3-dihydro- 1 1H-i 4 -benzodiazepin-2-one 3 2 -methyphenoxy)acety)Larny I)ino-2, 3-dihydro- 1 1 H-i 4 -benzodiazepin-2-one 4 -methoxyphenoxyacetyl>L.alaninl)am ino-2 ,3-dihydro- 1 I H- 1, 4 -benzodiazepin2one 3 -(phenylsulfonyl)propionyl)>L.alaninyl)amino- 2 ,3-dihydro- 1 methyl-5-phenyl -1 H-i 1, 4 -benzodiazep in..2 -one 834 (S)-3-(N'-2mtoyheyaey)Lalnnla o2 .3-dihydro- 1 -methyl- 1H- 1, 4 -benzodiazepin- 2-one 3 2 -bromophenylaceyl)L-alaniny)mino- 2 ,3-dihydro- 1 phenyl-1H-1 4 -benzodiazepin-2-one -(p-isopropyl phenylacetyl)-L-alaniny l)amino-2 ,3-dihydro- 1- 1H-i, 4 -benzodiazepin-2-one 4 -penterloyl)-L-alaninyl)amino-2 ,3-dihydro-l1-methy)-5-phenyl- 111-1 4 -benzodiazepin-2-one 4 -hydroxyphenoxyacetyI-Lalaninly)mno 2, 3-dihydro- 1 IH- 1, 4 -benzodiazepin-2-one 4 -oxopentanoyI)-L-alaninyl)amino-23.dihydro- I phenyl- 1H- 1 4 -benzodiazepin-2-one 2 -hydr oxyphenylacetyl)L-aaniny)mino- 2 ,3-clihydro- 1-methyl- 5-phenyl- 11- 1 4 -benzodiazepin-2-one 0. 0 4 -dimethoxyphenylacetyl)yL-alannl)amino- 2 ,3-dihydro- 1 methyl-5-phenyl-l1H-i 4 -benzodiazepin-2-one 3 4 -methoxybenzoyl)propionyl)L-alannyl)amino-2, 3-dihydro- 1 methyl-5-phenyl-l1H-i, 4 -benzodiazepin-2-one '-(thiophene-3-acetyl)-L-alaninyl)amjfl 0 3-dihydro- I phenyl- 1 H- 1, 4 -benzodiazepin-2-one 6 -phenylhexanoylI)-L-aaniny I)mino2 3-dihydro- 1 -methyl1-5 phenyl- 1 H-i 4 -benzodiazepin-2-one '-(isovalery I)-L-alaninyl)an-ino-2 ,3-dihydro- 1 -methyl-5-pheny I- I H- 1 4 -benzodiazepin-2-one -trifluorophenylacetyl)L-alannyl)amino- 2 ,3-dihydro- 1- 1H-i 4 -benzodiazepin-2-one ,-trifluorophenylacetyl>L-alaninyl)amino-2, 3-dihydro- 1 1 H-i 4 -benzodiazepin-2-one 1 -adamantaneacety I)-L-alaninyl) arnino-. 2,3-d ihydro- 1 phenyl- 1 H-i ,4-benzodiazepin-2-one 6$J '-(cyclohexanepentanoy)L-aaninyl)amino- 2 ,3-dihydro- 1 phe ny I-IH-1, 4-be nodiazepin-2-one 73 h, I 835 2 -thiopheneacetvI)-L-phenylgycinyly)mno-2.3-dihydro- 1 -methyl- IH-1, 4 -benzodiazep in-2 -one 3 3 -(trifuoromethyl)phenylacetyl)yLphenylglycinyl)amino. 2 3- dihydro- 1 -methyl-5-phenyl- 11-1 4 -benzod iazepin-2 -one ,S-difluorophenyacetyl)iLphenylglycinyI)amino-2.3-dihydro- I1- 1 H-i1, 4 -benzodiazep in-2 -one 3 -tolylacetyI)-L-phenylglyciny1)amino-2, 3-dihydro- 1 phenyl- 1 H- 1, 4 -benzodiazepin-2-one 3 -fluorophenylacetyl)yLphenylglyc inyl)amino-2 ,3-dihydro- 1 1 H-i 1, 4 -benzodiazep in-2 -one 3 -bromophenylacetyl)-L-phenylglycinyl)amjflo- 2 ,3-dihydro- 1 methyl-5-phenyl-l1H-i 1, 4 -benzodiazepin-2 -one 3 -chlorophenylacetyl)yLphenylglycinl)amino- 2 ,3-dihydro- I1- 20 methyl-5-phenyl- 1 H-i 1, 4 -benzodiazep in-2 -one *few *064 4 -methylenedioxyphenylacetyl>L-phenylglycinl)amjfo- 2 ,3 1H- 1 4 -benzodiazepin-2-one '-(phenylmercaptoacetyl)Lphenylglycinl)mio- 2 ,3-dihydro- 1- 1H-i 4 -benzodiazepin-2-one '-(acetyI)-L-phenylglyciny)mino-2 ,3-dihydro- 1 30 1 H-i 4 -benzodiazepin-2-one -('(35-bis(trifluoromethyl)phenylacety IL-phenylg lyc inyl) aino-. 2, 3-dihydro-l1-methyl-5-phenyl- 1H-i 4 -benzodiazepin-2-one -((methylthio)acetyl)-L-phenylglycinyl)amjflo- 3-dihydro- 1- 35 methyl-5-phenyl-lH.. 1 4 -benzodiazepin-2-one -peoyaey)Lphnllcny mn-,3-dihydro- 1 phenyl- IH- 1 4 -benzodiazepin-2-one (S--N-peylctl -hnlgyiy~m 3-dihydro- 1 phenyl-i1H- 1 4 -benzodiazepin-2-one (S--N-ccoexlctl -hnygyiy~m 3-dihydro- 1 -methyl- 5-phenyl-1IH- 1, 4 -benzodiazepin-2-one us(S)-3-(N ,-difluorophenyacety)iLphenylglyciny)mino- 2 .3-dihydro- 1 methymty -5-phenyl. 1 H- 1, 4 -benzodiazepin-2-one 836 '-(bezo[ bjtio hiop-aeyl-hen lgactpL..io-.-ihdo I11-1 4 -benzodiazepin2-one '-(benzoylformnyl)-Lphenylglycinyl)amino. 2 3-dihydro- 1 phenyl- 1 H- l. 4 -benzodiazepin.2-one 6 -difluorophenylacetyl)>Lphenylg lycinyl)axno2, 3-dihydro- I1- 1H 1, 4 -benzodiazepin..2-one 2 4 -difluorophenylacetyi).Lphenylglycinyl)mino-2 .3-dihydro- I1- 1H-i1, 4 -benzodiazepin2-one 4 -difluorophenylacetyI)-L-phenylgylyy)ajflo-2,3-dihydro- 1 methyl-5-phenyl.. 1H- i. 4 -benzodiazepin.2-one ~I)-L-phenylgyciny)mino 2 ,3-dihydro- 1 -methy 1 H- l. 4 -benzodiazepin.2-one (S--N-hpaol--h yllcnlaio23dhdo phenyl-l1H-i, 4 -benzodiazepin2one 4 2 -thienyl)butryl )-L-phenylglycinyl)amjfl 0 3-dihydro- 1 methyl-5-phenyl 1 H- l, 4 -benzodiazepin2one -5mtyhxnol--hnl yiy~m 3-dihydro- I1- methyl-5-phenyl.. 1H-i 4 -benzodiazepin2one '-(hydrocinnamyl).L-phenylglyc inyl)amino-2 ,3-dihydro- i-methyl-S phenyl-1H- l. 4 -benzodiazepin2one '-(cyclopentylacetylLphenylgycyl)no 2 ,3-dihydro- 1-methyl :5-phenyl- 1H-i 4 -benzodiazepin2one -poiny)Lpenllcny m 3-dihydro- 1 35 phenyl-1H-1 4 -benzodiazepin2one 4 ,5tilurpenlcty)Lphnllyiy ai2, 3-dihydro- I1-methyl-5-phenyl.1IH-1 4 -benzodiazepin.2.one 4 -phenylbutyryl)-Lphenylglyc inyl)amino-2, 3-dihydro- 1 -methyl- 5-phenyl-1H-i 4 -benzodiazepin.2-one 3-(N 2 -thiopheneacetylyL-alaniny l)amino-2, 3 -dihydro-5-phenyl. 1 trifluorobutyl1)- 1 H- l. 4 -benzodiazepin2-one ~jsp~3-(N 2 -thiopheneacetylyL-alaninyI)amino- b( 2 -oxo-2-phenylethyl)-2 ,3- -pheny I.-I HI- 1, 4 -benzod iazep in2-one 837 3-(N 2 -thiopheneacetyl)-L-alaninyl)amino- 1 -methyl-2 ,3-dihydro-s thiazolyl)-lIH-l 4 -benzodiazepin-2-one 3-(N -2tipeecey)Laaiy~aio7clr-, 3-dihydro. 1 -methyl- 5-phenyl- 1H-i 4 -benzodiazepin-2-one 2 -thiopheneacetyl).L.alaninyl)amino7chloro5(2-chiohy) 2,3- dihydro- 1 -methyl- IH- 1 4 -benzodiazepin-2-one 3-(N 2 -thiopheneacetyl)..L.alaninyl)amino-5-2-tenly) 2, 3-dihydro- 1 methyl- I H- 1, 4 -benzodiazepin-2 -one 3-(N 2 -thiopheneacetl)-Lalaninyl)mino-5cyc~ohexyl- 2 ,3-dihydro- 1 methyl- I H-i 4 -benzodiazepin-2-one 2 -thiopheneacetyl)-L-alaninyl)amino-7..bromo-5 -(2-fluorophenyl)-2 ,3- dihydro- 1 -methyl-i H-1, 4 -benzodiazepin-2-one 3-(N 2 -thiopheneaceyl)Lalainyl)>amino)- 2 4-dioxo- 1, 5-bis-(2,2- dimethylpropyl)-2,3 ,4 ,5-tetrahydro- 1H- 1 ,S-benzodiazepine .5-difluorophenylacetyl)Lalainyl)mino- 2 3 -dihydro-5-phenyl- 1 ,4-trifluorobutyl)- 1 H-i 4 -benzodiazepin-2-one 25 3-(N ,-difluorophenyaceyl)L-aaninyl)mino- I 2 -oxo-2-phenylethyl)- 2, 3-dihydro-5-phenyl- 1H-i, 4 -benzodiazepin-2-one 3-(N .S-difluorophenylacetyl-L-alainyl)aniino-. I-methyl-2, (2-thiazolyl)-lH-1 4 -benzodiazepin-2-one 3-(N S-difluorophenylacetyl)>L.alannyl)amin 0 7-chloro- 0 2, 3-dihydro- I1- methyl-5-phenyl- iH- 1 4 -benzodiazepin-2-one 3-(N S-difluorophenylacetyl)Lalaninyl)amino7chloro-5( 2 chlorophenyl)-2 ,3-dihydro- i-methyl-i H-i 4 -benzodiazepin-2-one 3-(N ,-difluorophenylacetyl)Iaaniny)mino5(2-thienyl)-2 ,3- 0 0 0dihydro- 1-methyl-i H-i 4 -benzodiazepin-2-one 3-(N .5-difluorophenylacetyl)-L..aaninyl)amino-5cycloeyl 2,3- dihydro- i-methyl-i H-i 4 -benzodiazepin-2-one 3-(N .5-difluorophenylacetyl)Lalaninyl)amino7bromo-5( 2 fluorophenyl)-2 ,3-dihydro- i-methyl-i H-i 4 -benzodiazepin-2-one jAN3J ,5-difluorophenylacetyl-Lalaninyl)amino-)2 ,4-d ioxo- 1,5-bis-(2 ,2- %imethylpropyl)-2 ,3 ,4,5-tetrahydro- 1H-i 838 3-(N 3 -fluorophenylacetyl)-L-alaninyl)amino-2, 3-dihydro-5-phenyl- I1- (4 .4,4-trifluorobutyl)- 1 H-i 4 -benzodiazepin-2-one 3 3 fluorophenylacety I)-L-alaniny I)amino- I -(2-oxo-2-phenylethyl)-2 3- dihydro-5-phenyl- 1 H-i 4 -benzodiazepin-2-one 3-(N 3 -fluorophenylacetyl)-L-alaninyl)amino- 1 -methyl-2 ,3-dihydro-5-(2- thiazolyl)- 1 H-i 4 -benzodiazepin-2-one 3-(N -3furpeyactl--lnnl mn--hoo23-dihydro- 1- 1 4 -benzodiazepin-2-one 3-(N 3 -fluorophenylacetyl)-L-alaninyl )amino-7-chloro-5-(2-chlorophenyl)> 2, 3-dihydro- 1 -methyl-i 1H-i 1, 4 -benizodiazepin-2 -one 3-(N 3 -fluorophenylacetyl)-L-aaniny)amino5-(xffiieny1)-2.3-dihvdro- I1- methyl- IH-1 4 -benzodiazepin-2-one 3 -fluorophenylacetyl)-L-aaniny)amino5cyclohexy 1-2.3 -dihydro- 1- methyl-1H-i 4 -benzodiazepin-2-one 3-(N -3furpeyaey)--lnnlaio7bom--2furpey) 2, 3-dihydro- 1 -methyl-i1 H-i 4 -benzodiazepin-2-one 3-(N 3 -fluorophenylacetyl)-L-aaniny)arnno)2 ,4-dioxo- 1, 5 -bis-(2 .2- dimethylpropyl)-2 ,3,4 ,5-tetrahydro-l1H-i 3-(N '-(methylthio)acetyl)-L-alaniny)amino.2 3-dihydro-5-phenyl- 1 tnifluorobutyl)-1H- 1 4 -benzodiazepin-2-one 3-(N '-(methylthio)acetyl)-L-alaninyI)arnino 1 -(2-oxo-2-phenylethyl)-2.3 dihydro-5-phenyl-l1H-i .4-benzodiazepin-2-one 3-(N '-(methylthio)acetyl)-L-alaniny)mino- 1 thiazolyl)-1H-i 4 -benzodiazepin-2-one -mty2,3diyr5(- -(methylthio)acetyl)-L-alaninyl)arnino7chlor-2 3-dihydro- 1-methyl- 1H- 1 ,4-benzodiazepin-2-one 3-(N '-(methylthio)acetyl)-L-alaninyl)amino7chloro-5(2-chloropheny 0-2,3- dihydro-i-methyl-iH 1, 4 -benzodiazepin-2-one 3-(N '-(methylthio)acetyl)-L-alaninyl)amino5(2-thienyl-2 3-dihydro- 1 methyl-i 1H-i ,4-benzodiazepin-2-one IS 3-(N '-(methylthio)acety)Lalaniny)amino5cyclohexyl-2, 3-dihydro- 1- methyl-lH-1,4-benzodiazepin-2-one 839 3-(N '-(methylthio)aceyl)LalaninyI)amino7bromo5(2fluorophenl)- 2 .3- dihydro- 1 -methyl- I H-i 1, 4 -benzodiazep in-2 -one 3-(N '-(methylthio)acetyl)-L-alaninyl-amino-)2 .4-dioxo- 1 ,5-bis-(2, 2- dimerhylpropyl)-2,3 .4,5-tetrahydro- I H- 3-(N '-(phenylacetyl)-L-alaninyl)amino.2 .3-dihydro-5-phenyI- 1 trifluorobutyl)- 1H- 1 4 -berizodiazepin-2-one 3-(N '-(phenylacetyl)-L-alaninyl)amino- 1 2 -oxo-2-phenylethyl)-2, 3-dihydro- 1 H-i 4 -benzodiazepin-2-one 3-(N '-(phenylacetyl)-L-alaninyl)amino- I -methyl-2 .3-dibydro-5-(2-thiazolyl iH-i 1. 4 -benzodiazepin-2 -one 3-(N '-(phenylacetyI)-L-alaninyl)amno-7-chloro-23-dihydro- I -methyl-- phenyl- 1 H-i 4 -benzodiazepin-2-one 3-(N '-(phenylacetyl)-L-alaninyl)amino-7choro5-(2-chlorophenvl) 2 3.. dihydro- I -methyl-i1 H-i 1, 4 -benzodiazepin-2-one 3 '-(phenylacety)-L-alaninyl)amino5(2 thienyl) 2,.3-dihydro- 1-methylI- 1H- 1 .4-benzodiazepin-2-one 3- (N-(hnlct I)Laaiy~mn- iccoey 2,-iyr-1-methyl 1 H-i, 4 -benzodiazepin-2-one 3-(N '-(phenylacetyl)Laaniny)amino7bromo-5-(2 fluorophenyl)-2, 3- dihydro- 1-methyl-i H-i 4 -benzodiazepin-2-one 3-(N '-(phenylacety1)-L-alaninyl)-amino-)2 ,4-dioxo-i ,5-bis-(2 ,2- dimethylpropyl)-2, 3,4, 5-tetrahydro- 1H-i ,S-benzodiazepine 3-(N '-(benzoylformyl)-L-aaninyl)amino23..dihydro5phenyl- 1 trifluorobutyl)- 1 H-i ,4-benzodiazepin-2-one 3-(N '-(benzoylformyl)-L-alaninyl)mino- 1 2 -oxo-2-phenylethyl)-2 .3- dihydro-5-phenyl- 1 H-i 4 -benzodiazepin-2-one 3-(N -(benzoylformyl)-L-alaninyl)amino 1 -methyl-2 ,3-dihydro-5-(2- thiazolyl)- 1H-i ,4-benzodiazepin-2-one 3-(N -(benzoylformyl)-L-alaninyl)amino..7-choro.2 ,3-dihydro- 1 -methyl -5 phenyl- 1iH- 1, 4-benzodiazepin-2-one Sdihydro- i-methyl-i H-i 4 -benzodiazepin-2-one 840 3-(N '-(benzoylformyI)-Lalaninyl)amino5(2-thienyl) 2, 3-dihydro- 1 -methyl- I1H- 1, 4 -benzodiazepin-2 -one 3-(N '-(benzoylformy)Laaniny)amino5cycohexy2 3 dhdr I -methyl- 1 H- 1 4 -benzodiazepin-2-one 3-(N '-(benzoylfornyl)Lalaninyl)amino7bromo-5( 2 -fluorohy)-2,3- diliydro- 1 -methyl-i1 H-i 4 -benzodiazepin-2-one -(benzoylformy)Lalaniny)amino)-2,4-dioxo- 1, 5-bis-(2 .2- dimethylpropyl)-2 ,3 ,4,5-tetrahydro- 1 H-i1, 3-(N '-(butyry l)-L-alaninyl)amino-2, 3 -dihydro-5 -phenyl- 1 trifluorobutyl)- 1 H- 1,4-benzodiazepin-2 -one 3-(N '-(butyryI)-L-alaninyl)amino- 1 2 -oxo-2-phenylethyl)-2 phenyl- 1 H-i 1, 4 -benzodiazep in-2 -one 3 -(N'-(butyry)-L-alaninyl)amino- 1 -methyl-2 ,3-dihydro-5-(2-thliazolyl)- I H- 1 4 -benzodiazepin-2-one 3-(N '-(butyrl)-L-alaninyl)amino7..chJoro-~, 3-dihydro- 1 h -m 1 H-i 4 -benzodiazepin-2-one 3('-(butyrl)Lalaninyl)amino-7-choro5(2-chlorophenyl), ,3-dihydro- 1-methyl-1H-i 4 -benzodiazepin-2-one 3 -(N'-(butyryl)-L-alaniny1)amino..s.(2-thiel)-2, 3-dihydro- 1-methyl- 1H- 1 4 -benzodiazepin-2-one 3-(N '-(butyryl)-L-alaninyl)amino-5-cyclohexyl-2 ,3-dihydro- i-methyl-i H- 1 4 -benzodiazepin-2-one '-buyrl)L-.anny.ain-7J-rmo52fuorop eny)., 3-dihydro- 1 methyl-lH-1,4-benzodiazepin-2. 0 ne 3-(N '-(butyryI)-L-alaninyl)-amino-)2 ,4-d joxo- 1,5-bis-(2 ,2-dimethylpropyl)- 2,3,4, 5-tetrahydro- 1 H-i 1, 3-(N 4 2 -thienyl)buyry)-L-alaninyl)amino, ,3 -dihydro-5-phenyl- 1 4-trifluorobutyl)y I. H-i1, 4 -berlzodiazepin-2-one 3-(N 4 2 -thienyl)butyryl)-L-alaninyl)amino- i-( 2 -oxo-2-phenylethy 1)-2 ,3- I H- 1, 4 -benzodiazepin-2-one US 3-(N 4 2 -thieny)buyry)Lalaninyl)amino- 1 -methyl-2, 3-dihydro-5-(2- ~V\thxazolyl)- 1H- 1 4 -berizodiazepin2one
841-- -(4-(2-thienyl)butyryl)-L-alaninyI)amino-7-chloro-2 ,3-dihydro- I1- IH-i 1,4-benzodiazep in-2 -one 3-(N 4 2 -thienyl)butyryl)-L-alaninyl)amino-7-chloro--(2-cfioropheny I)- 2, 3-dihydro- 1 -methyl- I H-i 1,4-benzodiazepin-2 -one -(4-(2-thienyl)butyryl)-L-alaninyl)amino-5-(2-Ehienyl)-2 ,3-dihydro- 1 methyl-i1 H-i ,4-benzodiazepin-2-one 4 -(2-thienyl)butyryl)-L-alaninyl)amino-5-cyclohexy-2 3-dihy~iro- I1- methyl-i H-i .4-benzodiazepin-2-one 3-(N 4 -(2-thienyl)butyry)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)- 2, 3-dihydro- i -methyl-i1 H-i 1,4-benzod iazepin-2 -one 3-(N 4 -(2-thienyl)butyryl)-L-alaninyl)-amino-)-2 ,4-dioxo-1 ,5-bis-(2 2- dimnethylpropyl)-2 ,3 ,4 ,5-tetrahydro- 1 H-1, 3-(N '-(cyclopentylacetyl)-L-alaninyflamino-2 ,3-dihydro-5-phenyl- 1 trifluorobutyl)- 1 H-i ,4-benzodiazepin-2-one 3-(N '-(cyclopentylacetyl)-L-alaninyl)amino- 1 -(2-oxo-2-phenylethyl)-2 ,3- 1H- 1 ,4-benzodiazepin-2-one 25 3-(N'-(cyclopenrylacetyl)-L-alaninyl)amino- I -methyl-2,3-dihydro-5-(2- thiazolyl)-iH- 1,4-benzodiazepin-2-one 3-(N '-(cyclopentylacetyl)-L-alaninyl)amino-7-chloro-2 ,3-dihydro- i-methyl- iH- 1,4-benzodiazepin-2-one 3-(N '-(cyclopentylacetyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2 .3- dihydro- 1 -methyl- I H-i ,4-benzodiazepin-2-one 3-(N '-(cyclopentylacetyl)-L-alaninyl)amino- 5-(2-thieny l)-2 ,3-dihydro- 1- methyl-i H-i ,4-benzodiazepin-2-one -(cyclopentylacetyl)-L-alaninyl)amino-5-cyclohexyl-2 ,3-dihydro- 1 methyl- I H-i ,4-benzodiazepin-2-one 3-(N '-(ylpnyactl--lniy~mn--boo5(.lurpey)3- dihydro- 1 -methy1-1 H-i 1,4-benzodiazepin-2-one N' -(cyclopentylacetyl)-L-alaninyl)-aniino-)-2 ,4-dioxo- 1, 5-bis-(2 .2- dimethylpropyl)-2 5-tetrahydro-l1H-i u s 3-(N -(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-2 ,3-dihydro-5-phenyl- 1 (4,4.4-trifluorobutyl)-iH- ,4-benzodiazepin-2-one 842 3-(N 3 -(trifluoromethyl)butyryl)-L-alaniny1)amino- 1 -(2-oxo-2- phenylethyl)-2 ,3-dihydro-5-phenyl- 1 H-i 4 -benzodiazepin-2-one 3-(N 3 -(trifluoromethyl)butyry)-L-alaninyl)amino. 1 -methyl-2 (2-thiazolyl)-i1H- 1,4-benzodiazepin-2-one 3-(N 3 -(trifluoromethyl)buryry)-L-alaninyl)amino-7-chloro-2 3-dihydro- 1 1 H-i ,4-benzodiazepin-2-one 3-(N 3 -(trifluoromethyl)burl)-L-alaninyl)amino..7-choro-5(2. chlorophenyl)-2.3-dihydro- 1 -methyl-i H-1, 4 -benzodiazepin-2-one dihydro- 1 -methyl-i 1H-i 1,4-benzodiazepin-2 -one 3-(N 3 -(trifluoromethyl)buryryl)-L-alaniny l)amino-5-cyclohexyl-2 .3- dihydro- i -methyl- I H-i 1,4-benzodiazepin-2 -one 3-(N 3 -(trifluoromethyl)butyyD-L-alaninyl)amino-7-bromo-5s-(2- fluorophenyl)-2 ,3-dihydro- i -methyl-i1 H-i ,4-benzodiazepin-2-one 3-(N 3 -(trifluoromethyl)butyryl)-L-alaninyl)-amino-)2 ,4-dioxo- 1, 2-dimethylpropyl)-2 ,3,4 ,5-tetrahydro- I H-i 3-(N 4 4 -trifluorobutyryl)-L-alaninyl)amino-2, 3-dihydro-5-phenyl- I1- (4,4 ,4-trifluorobutyl)- iH- 1,4-benzodiazepin-2-one 3-(N 4 -trifluorobutyryl)-L-alaninyl)amino- 1 -(2-oxo-2-phenylethyl)-2 ,3- 1 H-i ,4-benzodiazepin-2 -one 3-(N 4 4 -trifluorobutyryl)-L-alaninyl)amino i -methyl-2 ,3-dihydro-5-(2- thiazolylI)- I H-i 1,4-benzodiazepin-2 -one 4 -trifluorobutyyl)-L-alainyl)amino7chloro-2, 3-dihydro- I1- methyl-5-phenyl-l1H-i ,4-benzodiazepin-2-one 4 -trifluorobutyyl)-L-alaniny)amino7choro5(2-cmorophenyl)- 2, 3-dihydro- i -methyl- I H-i 4 -benzodiazepin-2-one 3-(N ,4-trifluorobutyryl)-L-alaninyl)amino5(2-thienyl>2 3-dihydro- 1 methyl-i1 H-i 1,4-benzodiazepin-2-one 3-(N 4 -trifluorobutyryl)-L-alaninyl)amino5cyclohexyi2 3-dihydro- I1- methyl- I H-i ,4-benzodiazepin-2-one -444tiloouyyl--lnnlaio7brm--2furpey) 2,3-dihydro-li-methyl-i H-i1, 4 -benzodiazepin-2-one 843 3-(N 4 4 4 -trifluoroburyryl)-L-alaniny)amino-)2 ,4-d joxo- 1. 5-bis-(2 .2- dirnethylpropyl)-2.3 ,4,5-tetrahydro- I11- 1, 3-(N '-(isovaleryl)-L-alaninyl)arnino-2 .3-dihydro-5-phenyl- 1 trifluorobutyl)-lH- 1, 4-benzodiazepin-2 -one 3-(N '-(isovaleryl)-L-alaninyl)axnino- 1 -(2-oxo-2-phenylethyl)-2 ,3-dihydro-5 phenyl- 1 H-i ,4-benzodiazepin-2-one 3-(N '-(isovaleryl)-L-alaninyl)amino- 1-methyl-2 ,3-dihydro-5-(2-Ehiazolyl)- 1H- 1,4-benzodiazepin-2-one 3-(N '-(isovaleryl)-L-alaninyl)amino-7-chloro.2 ,3-dihydro- 1 phenyl- 11-1 ,4-benzodiazepin-2-one 3-(N '-(isovaleryl)-L-alaninyl)amino-7-choro5(2chlorophel).2 3- dihydro- 1-methyl- 1H- 1,4-benzodiazepin-2-one 3-(N '-(Isovaleryl)-L-alaniny1)amino-5-(2-thienyJ)-2,3-dihydro- 1 -methyI- I H- 1 ,4-beflzodiazepin-2-one 3-(N '-(Isovaleryl)-L-alaniny1)amino-5-cyclohexylI2,3-dihydro- 1 -methyl-i1 H- 1 ,4-benzodiazepin-2-one 25 3-(N -ioaeyl--lnnl~mn--roo5( lorpey)23- dihydro- 1 -methyl-i1 H 1,4-benzodiazepin-2 -one 3-(N'-(isovaieryl)-L-alaninyl)-arino-)-2,4-dioxo-1,5-bis-(2,2- dixnethylpropyl)-2 5-tetrahydro-l1H-i, 3-(N'-(L-alpha-hydroxyisocaproyl)L-alaninyi)amino-2, 3-dihydro-5-pheny 1- 3-(N '-(L-alpha-hydroxyisocaproyl)-L-alarnnyl)amino. 1-(2-oxo-2- phenylethyl)-2 ,3-dihydro-5 -phenyl- 1 H-i 1,4-benzodiazepin-2-one '-(L-alpha-hydroxyisocaproyi)-L-alaniny) amino-. 1 -methyl1-2, -d ihydro- 5-(2-thiazolyl)- 1 H-i ,4-benzodiazepin-2-one 3-(N '-(L-alpha-hydroxyisocaproyl)-L-alaniny 1)amino-7-chloro-2 ,3 -dihydro- 1 -methyl-5-phenyl- 1H- 1,4-benzodiazepin-2-one 3-(N '-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-7ch1 0 ro-5(2- chlorophenyl)-2 ,3-dihydro- 1 -methyl-i1 H- 1, 4 -benzodiazepin-2-one diydo--mthl H-i 4 -benzodiazepin-2-one PC',I -844-- 3-(N '-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-5-cyclohexyl-2 .3- dihydro-i1-methyl- IH- 1, 4-benzodiazepin-2 -one 3-(N '-(L-alpha-hydroxyisocaproy1) -L-alaninyl1) amino- 7-bromo-5 fluorophenyl)-2 ,3-dihydro- 1 -methyl-ilI-1, 4-benzodiazepin-2 -one 3-(N '-(L-alpha-hydroxyisocaproyl)-L-alaninyl)-amino-)-2 ,4-dioxo- 1, (2,2-dimethylpropyl)-2 ,3,4 ,5-tetrahydro- 1 H-i1, +)-mandelyl)-L-alaninyl)amino-2 ,3-dihydro-5-phenyl- 1 trifluorobutyl)- 1H- 1 ,4-benzodiazepin-2-one 3-(N +)-rnandelyl)-L-alaninyl)amino- 1 -(2-oxo-2-phenylethyl)-2 .3- 1 H-i ,4-benzodiazepin-2-one 3-(N +)-mandelyl)-L-alaninyl)amino- 1 -methyl-2, 3-dihydro-5-(2- thiazolyl)- 1H- 1 ,4-benzodiazepin-2-one +)-mandelyl)-L-alaninyl)amino-7-chloro-2 ,3-dihydro- 1 -methyl :020 phenyl- 1H- 1 ,4-benzodiazepin-2-one 3-(N +)-mandelyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2, 3- dihydro-1I-methyl-iH- 1,4-benzodiazepin-2-one +)-mandelyl)-L-alaninyl)amino-5-(2-thienyl)-2 ,3-dihydro- 1- methyl-lH- 1,4-benzodiazepin-2-one 3-(N +)-mandelyl)-L-alaninyl)amino-5-cyclohexyl-2 ,3-dihydro- 1 methyl-i1H- 1 ,4-benzodiazepin-2-one 3-(N +)-mandelyl)-L-alaninyl)arnino-7-bromo-5-(2-fluorophenyl)-2 ,3- :dihydro- 1 -methy1-1 H-i ,4-benzodiazepin-2 -one O 3-(N 5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- I1- 35 (3-fluorobenzyl)- iH- 1,4-benzodiazepin-2-one 5-difluorophenylacetyl)-L- alaniny l)amino-5-phenyl-2 ,3-d ihydro- 1 (benzyl1)- 1iH- 1, 4-benzodiazepin-2-one .5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2 ,3-dihydro- 1 (4-terT-butylbenzyl)-l1H-i ,4-benzodiazepin-2-one 3-(N ,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl.2 3-dihydro- 1 (2-cyc lohexylethyl1)- 1 H-i 1,4-benzodiazepin-2 -one .S-difluorophenylacetyl)-L-alaniny I)amino-5-phenyl-2 ,3-dihydro- 1 (3,3 3-dimethy lbutyl)- 1 H-i 1,4-benzodiazepin-2 -one 845 3-(N 5-difluorophenylacetyl)-L-alaninyl)amino-5-phenylI2,.3-dihydro- 1 (1 -methoxycarbonyl Ii -phenyimethyl)- 1 H-i 1, 4 -benzodiazep in-2 -one 3-(N 5-difluorophenylacetyl)-L-alaniny I)arnino-5-phenyl-2 ,3-dihydro- I1- (2-ethylbutyl)-iH-1 ,4-benzodiazepin-2-one 3-(N ,5-difluorophenylacetyI)-L-alaninyI)amino-5-phenyl.2,3-dihydro- 1- (cyclohexylmethyl)- 1 H-i 1,4-benzod iazepin-2 -one 3-(N ,5-difluorophcnylacety1)-L-alaninyl)amino-5-phenyI2 .3-dihydro- I1- (2-phenylethyl)- 1 H-i1, 4-benzod iazepin-2 -one 3-(N ,5-difluorophenylacetyl)-L-alaniny)amino-5-phenyI2 3-dihydro- 1 (3-phenylpropyl)- 1H-1, 4-benzodiazepin-2-one 3-(N ,5-difluorophenylacetyI)-L-alaninyI)amino-5-pheny-2 3-dihydro- I (2-(N-phthaliniidyl)ethyl)- 1 H-i ,4-benzodiazepin-2-one 3-(N ,S-difluorophenylacetyl)-L-alaninyl)amino-5-.pheny.2 ,3-dihydro- 1 00oo 20 (2-biphenylImethyl)- 1 H-i1, 4-benzodiazepin-2 -one 3-(N 5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl.2 3-dihydro- 1 ooo* ((2-tetrahydrofuranyl)methyl)- 1 H-I ,4-benzodiazepin-2-one ,5-difluorophenylacetyI)-L-alaninyI)amino-5-pheny.2 3-dihydro- 1 1,4-benzodioxanyl)methyl)- 1 H-i ,4-benzodiazepin-2 -one 3-(N 5-difluorophenylacety1)-L-alaninyl)amino-5-pheny.2 ,3 -dihydro- 1 thieny l)methyl)- 1 H-i1, 4-benzodiazepin-2 -one 0:00 3-(N ,5-difluorophenylacetyl).L-alaninyI)amino-5-pheny1..2 ,3-dihvdro- 1- 3-dimethyl-2-oxo-propyl)-l1H-i ,4-benzodiazepin-2-one 3-(N 5-difluorophenylacety1)-L-alaninyI)amino-5-pheny.2 3 -dihydro- 1- (5-benzofurazanylmethyl)-l1H-i ,4-benzodiazepin-2-one 0 .S-difluorophenylacetyl)-L-alaninyI)amino-5-phenyl12,3-dihydro- 1 o 000* a ~(3-nnenoxvnrnnfl)- 1 H- ,-ezdapi2on 3-(N ,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2, 3-dihydro- 1 (6-(2-trifluoromethylquinolinyl)methyl)-l1H-1, 4-benzodiazepin-2-one ,5-difluorophenylacety1)-L-alaninyl)amino5-phenyl12,3-dihydro- 1 (2-methylbutyl)-l1H- 1, 4 -benzodiazepin-2-one ,-difluorophenylacetyl) -L-aaniny 1) amino pheny12 ,3 -dihydro- 1 ~\(ethyl)-1iH-i1,4-benzodiazepin-2-one 847 -(cyclopentylacetyl)-L-alaninyl)amino5-phenylI2,.3-dihydro- 1 chlorobenzo[b] thienyl)methyl)- 1H-I ,4-benzodiazepin-2-one 3-(N '-(cyclopentylacetyl)-L-alaninyI)arnino-5-phenyI2 3-dihydro-l1-(3,3- dimethyl-2-oxo-butyl)-iH-1 ,4-benzodiazepin-2-one 3-(N '-(cyclopentylacetyl)-L-alaninyl)amino5phenyl-2,3-dihydro- 1 benzofurazanylmethyl)- 1 H-i ,4-benzodiazepin-2-one 3-(N '-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro- 1 phenoxypropyl)- 1 H-i 1,4-benzodiazepin-2 -one 3-(N '-(cyclopentylacety1)-L-alaninyl)amino-5-phenyl.2, 3-dihydro- 1 trifluoromethylquinolinyl)methyl)- 1 H-i 1, 4-benzodiazepin-2 -one 3-(N '-(cyclopentylacetyl)-L-alaninyl)amino5phenyl-2,3-dihydro- 1 (cyclopropylmethyl)- 1H-1, ,4-benzodiazepin-2 -one 3 -(N'-(cyclopentylacetyl)-L-alaninyl)amino-5pheny.2 3-dihydro- 1 methylbutyl)- 1H- 1,4-benzodiazepin-2-one 3-(N -(cyclopentylacetyl)-L-alaninyl)arnino-5-phenyl-2, 3-dihydro- 1 -(ethyl)- 1 H- 1 ,4-benzodiazepin-2-one 3-(N '-(cyclopentylacetyl)-L-alaninyl)amino--phenyl.2 3-dihydro-l1-(4-(3 dimethylisoxazolyl)methyl)-l1H-i, 4-beazodiazepin-2-one 3-(N '-(cyclopentylacetyl)-L-alaninyl)amino.s-phenyl.2 3-dihydro- 1 -(propyl)- 1 H-i ,4-benzodiazepin-2-one 3-(N '-(cyclopentylacetyI)-L-alaninyl)amino-5-phenyI-2,3-dibydro- 1 methoxyethyl)- 1 H-i ,4-benzodiazep in-2-one 3-(N 4 4 -trifluorobutyryl)-L-alaninyl)amino5-phenyl-2, 3-dihydro- 1 35 (benzyl)-1H-i ,4-benzodiazepin-2-one see* 0. 4 4 4 -trifluorobutyryl)-L-alaninyl)amino-5-pheny.2 3-dihydro- 1 reni-butylbenzyl)- 1 H-i ,4-benzodiazepin-2 -one 3 4 4 4 -trifluorobutyryl)-L-aaniny)amino5pheny12 3-dihydro- 14-2- cyclohexylethyl)- 1H- 1 ,4-benzodiazepin-2-one 3-(N 4 4 -trifluorobutyry1)-L-alaninyl)amino5-pheny12 3-dihydro- 1 3-dimethylbutyl)- 1 H-i ,4-benzodiazepin-2 -one Fu 4 -trifluorobutyry1)-L-aaniny)amino5pheny12 ,3-dihydro- 1 (sopropyl)- 1H-i 1,4-benzodiazep in-2 -one 848 3-(N 4 4 4 -trifluorobutyryl)-L-alaninyl )amino-5-phenyl-2, 3-dihydro- 1 methoxycarbonyl -1 -pheny Imethy 1)-i H-i1, 4 -benzodiazepin-2 -one 3-(N 4 -trifluorobutyryl)-L-alaninyl)amino-5-pheny1-2 3-dihydro- 1 ethylbutyl)-1IH-1, ,4-benzodiazepin-2 -one 3-(N 4 4 -trifluorobutyryl)-L-alaninyI)amino-5-pheny.2 3-dihydro- I- (cyclohexylmethyl)- 1 H-i ,4-benzodiazepin-2-one 3 4 4 ,4-trifluorobutyryl)-L-aaniny)amino5pheny-2 3-dihydro- 1 phenyipropyl)- 1 H-i ,4-benzodiazepin-2-one 3 4 4 4 -trifluorobutyryI)-L-alaniny)amino5-pheny-2 3-dihydro- 1 biphenylmethyl)- 1iH- 1, 4-benzodiazepin-2 -one 3-(N 4 4 -trifluorobutyryI)-L-alaniny1)amino-5-pheny -2 ,3-dihydro- 1 thienyl)methyl)- 1H-I 4 -benzodiazepin-2-one 3-(N 4 -trifluorobutyryl)-L-alaniny)amino5pheny.2 3-dihydro- 1- 20 (3 ,3 -dixnethyl1-2-oxo-butyl)- I1H- 1, 4~-benzodiazepin-2 -one 3-(N 4 4 4 -trifluorobutyryl)-L-alaninyl)amino-5pheny.2 ,3-dihydro-l1-(5- benzofurazanylmethyl)-l1H-i ,4-benzodiazepin-2-one 25 3-(N 4 -trifluorobutyryl)-L-alaninyl)amino-5-phenyl.2 3-dihydro- 1-(3- phenoxypropyl)-l1H-i ,4-benzodiazepin-2-one 3-(N 4 -trifluorobutyryl)-L-alaninyl)amino.-.sphenyl.2 ,3-dihydro- 1 (2-trifluoromethylquinolinyl)methyl)- 1H- 1,4-benzodiazepin-2-one 3-(N'-(4,4,4-trifluorobutyryl)-L-aaninyl)amino5-pheny-2 ,3-dihydro- 1- 4 -trifluorobutyryI)-L-alaninyl)amo5pheny12 3-dihydro- 1 methylbutyl)-l1H-i ,4-benzodiazepin-2-one 4 4 4 -trifluorobutyryl)-L-alaniny)amino5phenylI2,-dihydr-l1 o* (ethyl)- iH-1 ,4-benzodiazepin-2-one 3-(N 4 -trifluorobutyryl)-L-alaninyl)amino5pheny-2 ,3-dihydro- 1 1H 1 ,4-benzodiazepin-2-one 3-(N 4 ,4, 4 -trifluorobutyryl)-L-alaninyl)amino5phenyl-2,3-dihydro- 1 (propyl)- 1 H-i ,4-benizodiazepin-2-one I 4 .4, 4 -trifluorobutyry I)-L-alaniny 1) amino pheny 1-2,3 -dihydro- 1- 4 methoxyethyl)-l1H-i 4 -benzodiazepin-2-one 9849 N +)-mandelyl)-L-alaninyl)-amino-)-2 ,4-dioxo- 1, 5-bis-(2 ,2- dimethyipropyl)-2,3 ,4 ,5-tetrahydro- 1H- 1 '-(N-pyrrolidinylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1 phenyl-1 H- 1 4-benzodiazepin-2-one 2 -chlorophenoxyacetyl)-L-alaninyl)amino-2,3. dihydro- 1 phenyl- 1H- 1,4-benzodiazepin-2-one 3-(N '-(2-thiopheneacetyl)-L-alaninyl)amino-2, 3-dihydro-l1-methyl-5-phenyI 1H- 1,4-benzodiazepin-2-one 3-(N 3 -(trifluoromethyl)phenylacetic)-L-alaniny l)amino-2 ,3-dihydro- 1- -1 H-i ,4-benzodiazepin-2-one 3-(N '-(4-tolylacetyl)-L-alaninyl)amino-2 ,3-dihydro-1 -methyl-5-phenyl -1 H- 1 ,4-benzodiazepin-2-one 3-(N 3 4 -methoxypheny)propiony)-L-alaniny)ampnoi-.3 -dihydro- 1 methyl-5-phenyl-1H- 1,4-benzodiazepin-2-one 3-(N ,5-difluorophenylacetyl)-L-alaninyl)amino-2 ,3 -dihydro- 1 phenyl 1iH-i ,4-benzodiazepin-2-one 3-(N '-(m-tolylacetyl)-L-alaninyl)amino-2 ,3-dihydro- 1-methyl-5-phenyl- iN- 1 ,4-benzodiazepin-2-one 3-(N '-(3-fluorophenylacetyl)-L-alaninyl) amino 2 ,3-dihydro- 1 phenyl- 1H- 1,4-benzodiazepin-2-one 3-(N '-(3-bromophenylacetyl)-L-alaninyl)amino-2, 3-dihydro-l1-methyl-5- phenyl-l1H-i ,4-benzodiazepin-2-one 3-(N '-(4-chlorophenoxyacetyl)-L-alaninyl)arnino-2, 3-dihydro- 1 *35 phenyl- 1H- 1 ,4-benzodiazepin-2-one 3-(N '-(2-naphthylacetyl)-L-alaninyl)ainino-2 ,3-dihydro- 1H-1 ,4-benzodiazepin-2-one 3-(N '-(3-methylphenoxyacetyl)-L-alaninyl)amino.2 3-dihydro-l1-methyl-5- phenyl- 1H-i ,4-benzodiazepin-2-one 3[N-( 4 -Inethoxyphenylacetyl)-L-alaninyl)amino] 3-dihydro- 1-methyl-S (2-pyridyl)-l1H-i ,4-benzodiazepin-2-one '-(2-thiopheneacetyl)-L-alaninyl)amino] 3-dihydro- 1 -methyl-5-(2- ph pyridyl1)- 1 H-i 1,4-be nzod iazep in-2 -one 850 .5-difluorophenylacetyl)-L-alaninyl)aminoj-2, 3-dihvdro- 1 -methyl- 5-(2-pyridyl)- IH-i ,4-benzodiazepin-2-one '-(3-bromophenylacetyl)-L-alaninyl)aminoj-2 ,3-dihydro- 1 -methyl-5-(2- pyridyl)-1H- 1 ,4-benzodiazepin-2-one 3-[(N'-(phenylmercaptoacetyl)-L-alaninyl)anino] 3-dihydro- 1 (2-pyridyl)- 1 H-i1, 4-benzodiazepin-2-one '-(4-ethoxyphenylacetyI)-L-alaninyl)amino]-2 ,3-dihydro- 1 -methyl-5-(2- pyridyl)- 1 H-i ,4-benzodiazepin-2-one '-(4-(trifluoromethyl)pheny Iacetyl)-L-alaninyl)amino} 3-dihydro- 1 methyl-5-(2-pyridyl)- 1 H-1, 4-benzodiazepin-2-one 3- ,5-bis(trifluoromethyl)phenylacetyl)-L-alaninyl)amino] -2,3 3-dihydro- 1 -methyl-5-(2-pyridy I H-i .4-benzodiazepin-2-one -((methylthio)acetyl)-L-alaninyl)amino] -2 ,3-dihydro- 1 -methyl-5-(2- pyridyl)- 1 H-i ,4-benzodiazepin-2-one '-(cyclohexylacetyl)-L-alaninyl)amino] 3-dihydro- 1 -methyl-5-(2- pyridyl)- 1 H-i ,4-benzodiazepin-2-one 25 3-[(N'-(pentafluorophenoxyacetyl)-L-alaninyl)anino] 3-dihydro- 1-methyl- 5-(2-pyridyi)- 1H-i ,4-benzodiazepin-2-one -(benzo[b]thiophene-3-acetyl)-L-alaninyl)amino 3-dihydro- 1- methyl-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 6-trimethylphenylacetyl)-L-alaninyl)amino] -2 ,3-dihydro- 1- methyl-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one *00 -(4-biphenylacetyl)-L-alaninyl)amino] 3-dihydro-lI-methy l-5-(2- pyridyl)-1H-i,4-benzodiazepin-2-one 00* 3- ,4-difluoropheny lacetyl)-L-alaninyl) amino] 3-dihydro- 1 -methyl- 5-(2-pyr-idyl)- 1 H-i ,4-benzodiazepin-2-one '-(4-(2-thienyl)butyryl)-L-alaninyl)amino] 3-dihydro- 1 -methyl-5- (2- pyridyl)- 1 ,4-benzodiazepin-2-one 3- -(5-methoyexanlpoyl)-L-alaninyI)amino] 3-dihydro- 1 (2 is mthy5-(2pyridyl)- IH- 1 ,4-benzodiazepin-2-one 85 1 6-difluoromandely])-L-alaninyl)axnino] 3-dihydro- 1 -methyl-5-(2- pyridyl)- 1H-1, ,4-benzodiazepin-2 -one '-(4-fluoromandelyl)-L-alaninyl)amino] -2,3-dihydro- 1 -methyl-5-(2- pyridyl)- 1 H-i 1,4-benzodiazepin-2 -one ,5-difluoromandelyl)-L-alaninyl)aminol-2 ,3-dihydro- 1 -methyl pyridyl)- 1H-1 ,4-benzodiazepin-2-one 6-trifluorophenylacetyl)-L-alaninyl)aminoj 3-dihydro- 1 methyl-5-(2-pyridyl)- 1 H-i ,4-benzodiazepin-2-one 4 -fluoro-2-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino] -2,3 dihydro- 1 -methyl-5-(2-pyridyl)- 1 H-i ,4-benzodiazepin-2-one ,4,4-trifluorobutyryl)-L-alaninyl)amino]-2 ,3-dihydro- 1 -methyl-5-(2- pyridyl)-l1H-i ,4-benzodiazepin-2-one 4 -isopropylphenylacetyl)-L-alaninyl)aminoj 3-dihydro- 1 -methyl-S 20 (2-pyridyl)-l1H-i ,4-benzodiazepin-2-one too*3- -(beta-phenyllactyl)-L-alaninyl)amino] 3-dihydro- 1 -methyi-5-(2 pyridyl)- 1 H-i ,4-benzodiazepin-2-one '-(mandelyl)-L-alaninyl)aniino]-2,3-dihydro-l1-methyl-5-(2-pyridyl)- iH- 1 ,4-benzodiazepin-2-one 3- '-(4-chloromandelyl)-L-alaninyl)amino] 3-dihydro-l1-methyl-5-(2- pyridyl)- 1H- 1,4-benzodiazepin-2-one -(isovaleryl)-L-alaninyl)amino] 3-dihydro-l1-methyl-5-(2-pyridyl 1H- 1 ,4-benzodiazepin-2-one 3- ,5-trifluoropheny lacetyl)-L-alaninyl)aminol -2,3 3-dihydro- 1 methyl-5-(2-pyridyl)-1IH- 1,4-benizodiazepin-2-one 3- 3 -methylthiopropionyl)-L-alaninyl)amino]-2 ,3-dihydro-l1-methyl-5- (pyridy H-1,4-benzodiazepin-2-one 3 -irphenylactyl)-L-alaninyl)amino]-2 3-dihydro--methyl-5-(2- pyridyl)- 1H- 1,4-benzodiazepin-2-one I". 852 3-[(N'-(4-methocyphenylacetyl)-L-alaninyl)amino-2 3-dihydro- 1 -(3,3 dimnethyl-2-oxobutyl)- 5-(2 -pyridy H- 1, 4 -benzodiazep in- 2-one 3-[(N'-(2-thiopheneacetyl)-L-alannyl)amino] -2 .3-dihydro-l1-(3, 3-dimethyl-2- oxobutyl)- 5 -(2-pyridyl)- IH 1, 4- benzodilazep in-2 -one 3- ,5-difluoropheny lacetyl)-L-alaninyl) amino] -2,3 3-d ihydro- 1 (3,3 dimethyl-2-oxobutyl)- 5 -(2-pyridyl)- 1 H-i 1,4-benzod iazep in-2 -one '-(3-bromophenylacetyl)-L-alaninyl)amino]-2, 3-dihydro-l1-(3,3- dimethyl-2-oxobutyl)- 5-(2-pyridyl)-1H-1 4 -benzodiazepin-2-one '-(phenylmercaptoacetyl)-L-alaninyl)amino] -2,3-dihydro-l1-(3,3- dimethyl-2-oxobutyl)- 5-(2-pyridyl)-1H-1 4 -benzodiazepin-2-one 3 4 -ethoxyphenylacetyl)-L-alaniny1) amino] 2,3-dihydro- 1- dimethyl-2-oxobutyl)- 5 -(2-pyridyl)- IH 1, 4 -benzodiazepin-2 -one 3- 4 -(trifluoromethyl)phenylacetyl)-L-alaninyl)amino-2 3-dihydro- 1 3-dimethyi-2-oxobutyl)- 5-(2-pyridyl)- iN- 1,4-benzodiazepin-2-one 3- S-bis(trifluoromethyI)phenylacetyl)L-alannyl)amino] -2.3 -dihydro- eeo 1 ,3-dixnethyl-2-oxobutyl)- 5 -(2-pyridyl)- 111- 1, 4-benzodiazepin-2 -one 3- -((methylthio)acetyl)-L-alaninyl)amino] 3-dihydro-l1-(3, 3-dimethyl- 2-oxobutyl)- 5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one '-(cyclohexylacetyl)-L-alaninyl)amino] -2 ,3-dihydro-l1-(3 ,3-dimethyl-2- oxobutyl)- 5-(2-pyridyl)-l1H-i 4 -benzodiazepin-2-one 3- -(pentafluorophenoxyacety)-L-alaninyl)amino)..2 ,3-dihydro-l1-(3,3I- dimethyl-2-oxobutyl)- 5-(2-pyridyl)-l11-1 4 -benzodiazepin-2-one 3- -(benzo thiophene-3-acetyl)-L-alaniny)amino] 2,3-dihydro- 1 (3,3- :3 dA111L.Ly-2-oxobutyl) 5-I(-pyridyi)- in-1,4-benzodiazepin-2-one 6 -trimethylphenylacetyl)-L-alaninyl)amino] 3-dihydro-l1-(3,3- dimethyl-2-oxobutyl)- 5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one '-(4-biphenylacetyl)-L-alaninyl)amino] -2 ,3-dihydro-l1-(3, 3-dimethy1-2- oxobutyl)- 5-(2-pyridylI)- 1 H- 1, 4 -berizodiazepin-2 -one ,4-difluoropheny lacety1)-L-alaniny1) amino] 2 ,3-d ihydro- 1 dimethyl-2-oxobutyl)- 5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3- 4 -(2-thienyl)butyl)-L-alaninyl)amino] -2 ,3-dihydro-l1-(3 ,3-dimethyl-2- Soxobutyl)- 5 -pyridyl)- 1 H-i 1, 4 -benzod iazep in-2 -one 853 '-(5-methylhexanoyl)-L-alaninyl)amino] 3-dihydro- 1 3-dimethyl- 2-oxobutyl)- 5-(2-pyridyl)- 1H- 1 4-benzodiazepin-2-one 6 -difluoromandelyI)-L-alaninyl)aminoI-2 3-dihydro- 1 dimethyl-2-oxobutyl)- 5 -(2-pyridyl)- 1 H-i 1,4-benzodiazepin-2 -one 4 -fluoromandelyl)-L-alaninyl)amino]-2 ,3-dihydro-l1-(3 ,3-dirnethyl-2- oxobutyl)- 5-(2-pyridyl)- 1H-I ,4-benzodiazepin-2-one ,5-difluoromandelyl)-L-alaninyl)aminoy-2,3-dihydro-l1-(3,3- dimethyl-2-oxobutyl)- 5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-orne 3- 6 -trifluorophenylacetyl)-L-alaninyl)amino] 3-dihydro 1 diinethyl-2-oxobutyl)- 5-(2-pyridyl)-1H-1 ,4-benzodiazepin-2-one 3- 4 -fluoro- 2 -(trifluoromethyl)phenylacety)-L-alaninyl)aminoj -2,3- dihydro- 1-(3 ,3-dimethyl-2-oxoburyl)- 5-(2-pyridyl)- 1H- 1,4-benzodiazepin-2- one 4 4 ,4-trifluorobutyyl)-L-alaninyl)amino]-2,3-dihydro-l1-(3,3- dimethyl-2-oxobutyl)- 5-(2-pyridyl)-1H-1 ,4-benzodiazepin-2-one 3- 4 -isopropylphenylacetyl)-L-aaninyl)amino] 3-dihydro-l1-(3,3- dimethyl-2-oxobutyl)- 5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2-one 3- -(beta-phenyllactyl)-L-aianinyl)amino] 3-dihydro-l1-(3 ,3-dimnethyl-2- oxobutyl)- 5 -(2-pyridyl)- 1 H-i 1,4-benzodiazepin-2 -one '-(mandelyI)-L-alaninyI)amino]-2,3-dihydro-l ,3-dimnethyl-2- oxobutyl)- 5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3-('(4clrmadll: aaiylaio-2 .3-dihydro-l1-(3, 3-d'umethy1-2- 35 3- -(isovaleryl)-L-alaninyl)amino] 3-dihydro-l1-(3 ,3-dirnethyl-2- oxobutyl)- 5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2-one 5-trifluorophenylacetyl)-L-alaninyl)aminoj 3-dihydro-l1-(3,3- dimethyl-2-oxobutyl)- 5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one '-(3-methylthiopropionyl)-L-alaninyl)amino]-2, 3-dihydro- 1 dimethyl-2-oxobutyl)- 5-(2-pyridyl)- 1H-i 4 -benzodiazepin-2-one '-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino] 3-dihydro-l1-(3,3- dmethy-2-oxobutyl)- 5-(2-pyridyl)-l1H- 4 -benzodiazepin-2-one 854 '-(3-nitrophenylacetyl)-L-alaniny I)aminoj 3-dihydro- 1 3-dimethy I- 2-oxobutyl)- 5 -(2-pyridyl)- 1 H 1, 4 -benzod iazep in-2 -one '-(D-3-phenyllactyl)-L-alaninyl )amino] 3-dihydro-l1-(3, 3-dimethyl-2- oxobutyl)- 5-(2-pyridyl)-iH-1 4 -benzodiazepin-2-one 4 -methoxyphenylacetyl)-L-alaninyl)amino] 3-dihydro-l1-(2-N, N- diethyl aminoethyl)- 5 -pyridyl)- 1 H 1, 4 -benzodiazepin-2 -one 3-[(N'-(2-thiopheneacetyl)-L-alaninyl)amino] 3-dihydro-l1-(2-N ,N- diethylaminoethyl)-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3 "-acetylI-N -pheny Iglycinyl)L-alaninyl) amino]2 ,3 3-dihydro- 1 N, N-diethyl aininoethyl)- 5-(2-pyridyl)-l1H-i, 4-benzodiazepin-2-one ,S-difluorophenylacetyI)-L-alaninyl)amino] 3-dihydro-l1-(2-N, N- diethyl aminoethyl)- 5-(2-pyridyl)-l1H-i ,4-benizodiazepin-2-one 3- 3 -bromophenylacetyl)-L-alanjnyI)amino] 3-dihydro-l1-(2-N, N- diethyl aminoethyl)- 5-(2-pyridyl)-l1H-i ,4-benzodiazepin- 2-one -(phenylmercaptoacetyl)-L-alaninyl)amino] 3-dihydro-l1-(2-N,N- diethyl aminoethyl)- 5 -(2-pyridyl)- 1 H-i1, 4 -benzodiazepin-2 -one 25 4 -(trifluoromethyl)phenylacetyl)-L-alaninyl)amino] 3-dihydro- 1 N, N-diethyl aminoethyl)- 5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3- ,S-bis(trifluoromethy1)phenylacetyI)-L-alaninyl)amino] 3-dihydro- 1 N-diethyl aminoethyl)- 5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3- -(cyclohexylacetyl)-L-alaninyl)amino] 3-dihydro- N-diethyl aminoethyl 5-(2-pyridyl)- iH- 1,4-benzodiazepin-2-one -(pentafluorophenoxyacetyl)-L-alaninyl)amino]-2 ,3-dihydro- 1 N- diethyl aminoethyl)- 5-(2-pyridyl)-l1H-I ,4-benzodiazepin-2-one 3- -(benzo[b]thiophene-3-acetyl)-L-alaninyl)amino) -2,3 -dihydro- 1 N, N-diethyl aminoethyl)- 5-(2-pyridyl)- 1H- 1,4-benzodiazepin-2-one 3 -[(N'-(benzoylformyl)-L-alaninyl)amino]-2 ,3-dihydro- 1 N -diethylI aminoethyl)- 5-(2-pyridyl)-l1H-i ,4-benzodiazepiii-2-one 4 -difluorophenylacetyl)-L-alaninyl)amino] 3-dihydro-l1-(2-N, N- diethyl arninoethyl)- 5-(2-pyridyl)-l1H-i 4 -benzodiazepin-2-one S 4 2 -thienyl)butyryl)-L-alaninyl)amino] -2 ,3-dihydro- 1 N- 3dilethyl aminoethyl)- 5 -(2-pyridyl)- 1H-i 4 -benzodiazepin-2-one 855 3-[(N'-(5-methylhexanoyl)-L-aianinyl)aniino]-2 .3-dihydro- 1 N-diethyl aminoethyl)- 5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2-one 3-('-(4-fluoromandelyl)-L-alaninyl)amino] 3-dihydro-l1-(2-N, N-diethyl aminoethyl)- 5-(2-pyridyl)- 1H- 1,4-benzodiazepin-2-one .5-difluoromandelyl)-L-alaninyl)amino] 3-dihydro-l1-(2-N, N- diethyl arninoethyl)- 5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2-one ,4-trifluorobutyry!)-L-alaninyl)amino] 3-dihydro-l1-(2-N, N- diethyl aminoethyl)- 5-(2-pyridyl)- 1 H-i 1,4-benzodiazepin-2 -one 3- 4 -isopropylphenylacetyl)-L-alaninyl)aminoj.2 3-dihydro-l1-(2-N ,N- diethyl aminoethyl)- 5-(2-pyridyl)-lIH-i ,4-benzodiazepin-2-one -(beta-phenyllactyl)-L-alaninyl)amino]-2 ,3-dihydro-l1-(2-N, N-diethyl aminoethyl)- 5-(2-pyridyl)- 1H- 1,4-benzodiazepin-2-one '-(mandelyl)-L-alaninyl)amino] 3-dihydro-l1-(2-N, N-diethyI aminoethyl)- 5-(2-pyridyl)-l1H-i, 4-benzodiazepin-2-one 3- '-(4-chloromandelyl)-L-alaniinyl)amino] 3-dihydro-1- N-diethyI aminoethyl)- 5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2-one 25 '-(isovaleryl)-L-alaninyl)axnino]-2 ,3-dihydro- 1 N-diethyl .00.aminoethyl)- 5-(2-pyridyl)- 1H- 1,4-benzodiazepin-2-one ,S-trifluorophenylacetyl)-L-alaninyl)amino) 3-dihydro-l1-(2- N ,N-diethyl aminoethyl)- 5-(2-pyridyl)-1H- 1, 4-benzodiazepin-2-one 3- 3 -methylthiopropionyl)-L-alaninyl)amino] 3-dihydro-l1-(2-N, N- diethyl aminoethyl)- 5-(2-pyridyl1)- 1 H-i14bnoizpn2-n 3-[N-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino) 3-dihydro- 1 N,N-diethyl aminoethyl)- 5-(2-pyridyl)-1H-1 ,4-benzodiazepin-2-one 3 -nitrophenylacetyl)-L-alaminyl)aminoI 3-dihydro- 1 N-diethyl aminoethyl)- 5-(2-pyridyl)-l1H-i ,4-berizodiazepin-2-one 000 40 3-[(N'-(D-3-phenyllactyl)-L-alaninyl)amino]-2 ,3-dihydro- 1 ,N-diethylaminoethyl)- 5-(2-pyridyl)- 1H- 1 4 -benzodiazepin-2-one 3- ,5-difluorophenylacetyl)-L-alaninyl] -ainino-2 ,4-dioxo- 1, (2-methylpropyl)-2 5-tetrahydro- 1 H-i1, .5-difluorophenylacetyl)-L-alaninyl) -amino-2 ,4-dioxo- 1, (niethyl)-2,3,4, 5-tetrahydro- 1H-i, 856 .5-difluorophenylacetyl)-L-alaninyl j-amino-2 .4-dioxo- 1. (cyclopropylmethyl)-2 .3.4 ,5-tetrahydro- 1 H-i 3- .5-difluorophenylacetyl)-L-valinyl1] -amino-2 ,4-dioxo- 1. (2-merthylpropyl)-2 .3 4.5-tetrahydro- 1 H- 3-[N-(3.5-difluorophenylacetyl)-L-valinyl] -amino-2 .4-dioxo- 1, (methyl)-2,3 5-tetrahydro- 1 H- .5-difluorophenylacetyl)-L-valinyl] -amino- 2,4-dioxo- 1 (cyclopropylmethyl)-2 ,3,4 ,5-tetrahydro- 1H- 1, .5-difluorophenylacetyl)-L-norvalinyl] -amino-2 ,4-dioxo- bis-(2-methylpropyl)-2 ,3 4, 5-tetrahydro- 1 H-i .5-difluorophenylacetyl)-L-norvalinyl] -amino-2 .4-dioxo- bis-(methyl)-2 ,3 5-tetrahydro- 1 H-i -difluorophenylacetyl)-L-norvalinyl] -amino-2 ,4-dioxo- bis-(cyclopropylmethyl)-2 ,3 ,4,5-tetrahydro- 1 H- 3- .5-difluorophenylacetyl)-L-methioninyl] -amino-2 ,4-dioxo- 1. bis-(2-methylpropyl)-2 5-tetrahydro- 1H- -1 3-[N-(3.5-difluorophenylacetyl)-L-methioninyll-amino.2 4-dioxo- bi-mty)2345-erhdo -1 3- ,5-difluorophenylacetyl)-L-methioninyl] -amino-2 ,4-dioxo- bis-(cyclopropylmethyl)-2 p3,4, 5-tetrahydro-l1H-I. .5-difluorophenylacetyl)-L-phenylalaninyl)-amino-2,4-dioxo- 1 ,5-bis-(2-methylpropyl)-2,3 .4,5-tetrahydro-l1H-i. 3- (3 .5-difluoropheny lacetyI)-L-phenyla laniny 1] -amino- 2,4-d ioxo- 1, 5-bis-(methyl)-2 5-tetrahydro- 1 H- 1,5 -benzodiazepine .5-difluorophenylacetyl)-L-phenylalaninyl]pamino-2 4-dioxo- 5-bis- (cyclopropylmethy 1)-2 ,3,4,5 -tetrahydro- 1 H-i1, 5 -benzod iazep ine .5-difluorophenylacetyl)-L-phenylgiycinyl)yamino-2,4-dioxo- 1, 5-bis-(2-methylpropyl1)-2,3,. 4 ,5 -tetrahydro- 1 H-i1, 5 -benzodiazep ine 3 .5 Adifluorophenylacety I)-L-phenylg lyc iny 1] -am ino-2 .4-d ioxo- 1, 5-bis-(methylI)-2 5-tetrahydro- 1 H-i1, 5 -benzod iazep ine 3 .5-difluorophenylacetyI)-L-phenylglycinyll-amino-2 4-dioxo- 1 ,5-bis-(cyclopropylmethyl)-2 .3,..5-tetrahydro-l1H-i 857 3-[N-(3.5-difluorophenylacetyI)-(2-thienyl)glycineI -arnino-2 ,4-dioxo- 1 ,5-bis-(2-methylpropyl)-2 ,3 .4.5-tetrahydro- 1H -1 .S-difluorophenylacetyl)-(2-thienyI)glycine] -amino-2 ,4-dioxo- 1 ,5-bis-(methyl)-2 .3 4,5-tetrahydro- 18H- 1 .S-difluorophenylacety)-(2-thienyI)glycine] -amino-2 ,4-dioxo- 1, 5-bis-(cyclopropylmethyl)-2,3,4 .5-tetrahydro- I1H-i, .5-difluorophenylacety)-(3-thienyl)glycine]-ainino-2 ,4-dioxo- 1 ,5-bis-(2-methylpropyl)-2 ,3 5-tetrahydro- 18H- 3 difluoropheny lacety I)-(3-thieny)g yc ine amino-2 ,4-dioxo- 1 ,5-bis-(methyl)-2 ,3 .4.5-ren-ahydro- 1 H-i .5-difluorophenylaceyl)-(3- thienyl)glycjne] -amino- 2,4-di oxo- 1, 5-bis-(cyclopropylmethyl)-2 .3.4 5-tetrahydro- 1 H-i 1. 3-f N-(3 .S-difluorophenylacetyl)-L-threoninyl] -amino-2 .4-dioxo- bis-(2-methylpropyl)-2 ,3,4 ,5-tetrahydro- I H- S-difluorophenylacetyl)-L-tu-eoninyl] -amino-2 ,4-dioxo- 0* 1, 5-bis-(methyl)-2,3.4 ,5-tetrahydro- 1 H-i 0. 25 3- -difluorophenylacetyl)-L-lu-eoninylI -aino-2 .4-dioxo- 1, bis-(cyclopropylmethyl)-2 5-tetrahydro-1-, .S-difluorophenylacetyl)-L-ryrosiny I)-amino-2 ,4-dioxo- 1, (2-methylpropyl)-2 5-terrahydro-1H- 1, ,5-difluorophenylacety1)-L-tyrosinyl]>amino-2 ,4-dioxo- 1 (methyl)-2 5-tetrahydro- -difluorophenylacetyl)-L-tyrosinyl] -amino-2 ,4-d ioxo- 1,5 bis-(cyclopropylmethyl)-2,3 ,4 ,5-tetrahydro- 18H-1, 0 0' 3 -[N-(cyclopentylaceryl)-L-alaninyl] -amino-2 ,4-dioxo- 1, (2-methylpropyl)-2 5-terrahydro- 18-1,5 -benzodiazepine 00040 3- [N-(cyclopentylacetyl)-L-alaninylyamino-2,4-dioxo- 1, (methyl)-2,3 ,4 .5-tetrahydro-l1-,5-benzodiazepine 3 -[N-(cyclopentylacetyl)-L-alaniny1Iamino-2 4-dioxo- (cyclopropylmethyl)-2.3 .4.5-rerrahydro- 18-1, ,sr, 3 -[N-(cyclopentylacetyl)-L-valinyllamino-2.4-dioxo- 1 (2-methylpropyl)-2 .3,4 .5-terrahydro- 18-1, 858 3-[N-(cyclopenrylacetyl)-L-valinyl] -amino -2 .4-d ioxo- 1, (methyl)-2,3 5-tetrahydro- 1 H-1, S-benzodiazepine 3 -[N-(cyclopentylacetyl)-L-valinyl)-amino-2, 4-dioxo- 1, (cyclopropylmethyl)-2,3,,5-tetrahydro- 1 H-i1, 3 -[N-(cyclopentylacetyl)-L-norvaliny I]-amino-2 ,4-dioxo- 1, bis-(2-methylpropyl)-2 ,3 ,4,5-tetrahydro- I H-i 3 -[N-(cyclopentylacety)-L-norvauinyI]..amjno.2 ,4-dioxo- bis-(methyl)-2,3 ,4 ,5-tetrahydro- 1H- 1 3- [N-(cyclopentylacetyl)-L-norvalinyl] -arnino-2 ,4-dioxo- bis-(cyclopropylmethyl)-2 ,3,4,5 -tetrahydro- 1 H-i1, 3 -[N-(cyclopentylacetyl)-L-methioninyl] -amino-2 ,4-dioxo- bis-(2-methylpropyl)-2 p3,4, 5-tetrahydro- 1 H-i 1, 5 -benzodiazepine 3-N(ylpnyaey)Lmehoiy)aio24d o bis-(methyl)-2 ,3 ,4,5-tetrahydro- 1H- 1 3 -[N-(cyclopentylacety)-Lmethioninyl]>amno-24-diox bis-(cyclopropyimetliyl)-2,3,4, 5-tetrahydro-. 1 H-i ,5 -benzodiazepine 3-N(ylpnyaey)Lpeyaaiy]aio24doo 3- [N-(cyclopentylacety)-L-phenyalaninyl] -amino-2 ,4-dioxo- 1 ,5-bis-(methyl)-2 ,3 ,4,5-tetrahydro-1H- 1, 3- [N-(cyclopentylacetyl).Lphenylalaninyl] -amino-2 .4-dioxo- 1 ,5-bis-(cyclopropylmethyl).2 3,4, 5-tetrahydro-l1H-i 3- [N-(cyclopentylacetyl).Lphenylglycinyl] -amino-2 ,4-dioxo- 1, 5-bis-(2-methylpropyl)-2 ,3,4 ,5 -tetrahydro- 1 H-i1, 3 [N-(cyclopentylacety)-L-phenylglycinyl] -amino-2 ,4-dioxo- 1 ,5-bis-(methyl)-2 ,3 ,4,5-tetrahydro-l1H-i **40 3 [N-(cyclopentylacetyl).L-phenylglycinylI -amino-2 ,4-djoxo- 1, 5-bis-(cyclopropylmethyl)-2 5-tetrahydro- 1 H-i1, 3 [N.(cyclopentylacetyl)..(2-thienyl)glycine] -amino-2 ,4-dioxo- 1, S-bis-(2-methy lpropyl)-2 ,3 ,4,5-tetrahydro- 1 H- 1, S-benzodiazepine r~ 3 -[N-(cvclopentylacetyl)-(2-thienyl)glycine] -amino-2 .4-dioxo- 15-bis-(methyl)-2 ,3 ,4,5-tetrahydro-l1H-i 859 3 [N-(cyclopentylacetyl)-(2-thienyl)glycine] -amino-2 .4-dioxo- 1 .5-bis-(cyclopropylmethyl)-2 5-tetrahydro- 18H- 3 -[N-(cyclopentylaceryl)-(3-thienyl)glycinej-amjno-2,4-djoxo- 1 .5-bis-(2-methylpropyl)-2, 3 4.5-tetrahydro- 1 H-i 3- [N-(cyclopenrylaceryl)-(3-thienyl)glycinej -amino-2 ,4-dioxo- 1 ,5-bis-(methyl)-2 ,3 ,4,5-tetrahydro- 1 H-i1, 3 -[N-(cyclopentylacetyl)-(3-thienyl)glycine)-amno.2 ,4-dioxo- 1 ,5-bis-(cyclopropylmethyl)-2 ,3 5-tetrahydro- 1H- I 3- [N-(cyclopentylacetyl)-L-serinyl]-amino-2,4.dioxo- 1 (2-methylpropyl)-2, 4,5-tetrahydro- 1 H-i 3-[N-(cyclopentylacetyl)-L-threoninyl] -amino-2.4-dioxo- bis-(2-methylpropyl)-2 .3,4 ,5-tetrahydro- 18- 1 3- [N-(cyclopentylacetyl)-L-threoninyi] -amino-2 ,4-dioxo- 1, bis-(methyl)-2 5-tetrahydro- 18H-1,5 -benzodiazepine *3-[N-(cyclopentylacety)-L-threoniny]amino24-dioxo- bis-(cyclopropylmethyl)-2 ,3,4 ,5-tetrahydro- 1 H-i1, 3- [N-(cyclopentylacetyl)-L-tyros iny 1)]amino-2,4-dioxo- 1, .5-bis (2-methylpropyl)-2,3,4, 5-tetrahydro- 18-1, 3-[N-(cyclopentylacetyl)-L-tyrosinyl]-amino..2,4-dioxo-1,5- bis-(methyl)-2,3,4, 5-tetrahydro-1H- 1, 3-[N-(cyclopentylacetyl)-L-tyrosinyl) -amino-2 ,4-d joxo- 1,5 bis-(cyclopropylmethyl)-2 ,3,4 .5-tetrahydro- 1H- 1, ,4 ,4-trifluorobutryl)-L-alaninyl] -ainino-2 ,4-dioxo- 1, (2-methylpropyl)-2 ,3 ,4,5-tetrahydro- 18-1, 3 ,4 ,4-trifluorobutryl)-L-alaninyl] -amino-2 ,4-dioxo- 1, bis-(methyl)-2,3,4,5-tetrahydro-1H-1 3- ,4-trifluorobutry1)-L-alaninyl1 -amino.2 ,4-dioxo- 1, (cyclopropylmethyl)-2,3,4, 5-tetrahydro- 18H-1, 5 -benzodiazepine 3- 4 -trifluorobutryl)-L-valinyl] -amino-2 ,4-dioxo- 1, (2-methylpropyl)-2 5-tetrahydro- 1H- 1, 3- .4,4-trifluorobutrylI)-L-valinyl] -arnino-2 .4-dioxo- 1, ',,-(methyl)-2 ,3,4 .5-tetrahydro- 18H- 1,5 -benzodiazepine 860 ,4 ,4-trifluorobutryl)-L-valinyl]-amino-2 .4-dioxo- 1 (cyclopropylmethyl)-2 ,3,4 ,5-tetrahydro- 1 H-i1, 3-[N-(4,4,4-trifluorobutryl)-L-norvalinyl]-anino-2 ,4-dioxo- bis-(2-methylpropyl)-2 ,3 ,4,5-tetrahydro- 1 H-i 3- ,4 ,4-trifluorobutryl)-L-norvalinyl] -amino-2 ,4-dioxo- 1,5 bis-(methyl)-2 ,3,4 .5-tetrahydro- 1 H-i 3-[N-(4,4,4-trifluorobutryl)-L-norval inyl] -amino-2 ,4-dioxo- 1, bis-(cyclopropylmethyl)-2 5-tetrahydro- 1 H-i ,4-trifluorobutryl)-L-methioninyl]-amino-2 ,4-dioxo- 1, bis-(2-methylpropyl)-2,3 ,4,5-tetrahydro- 1 H-i 3- ,4 ,4-trifluorobutryl)-L-methioninyl] -amino-2 ,4-dioxo- 1,5 bis-(methyl)-2 ,3 ,4,5-tetrahydro- 1 H-1, 3-[N-(4,4,4-trifluorobutryl)-L-methioninyll-amino-2 ,4-dioxo- bis-(cyclopropylmethyl)-2 ,3 ,4,5-tetrahydro-l1H-i [N ,4 ,4-trifluorobutry I)-L-pheny lalaninyl1) -amino-2 ,4-d ioxo- 1, 5 -bis- (2-methy lpropyl1)-2 ,3,4 ,5 -tetrahydro- 1 H-i1, 5 -benzodiazep ine 3- ,4 ,4-trifluorobutryl)-L-phenylalaninyl) -arnino-2 ,4-dioxo- 1 ,5-bis-(methyl)-2 ,3 ,4,5-tetrahydro-iH- 1, ,4 ,4-trifluorobutryl)-L-phenylalaninyl1)-amino-2 .4-dioxo- 1, 5-bis-(cyclopropylmethyl)-2 5-tetrahydro-l1H-i ,4-trifluorobutryl)-phenylglycinyl] -amino-2 ,4-dioxo- -1 ,5-bis-(2-methylpropyl)-2 ,3 ,4 ,5-tetrahydro-iH- 1, 3- fN-(4 ,4 ,4-trifluorobutryl)-L-phenylglycinyl] -amino-2 ,4-dioxo- 35 1, 5-bis-(methyl)-2 ,3,4 ,5-tetrahydro-l1H-i, diox-1,-bi-(2metylpopyl-2,,4,-terahdrolH-,5-benzodiazepine 3- [N -(4,4,4-trifluorobutryl)-L- (2-thienyl)g lyc ine] -amino-2,4- d ioxo- 1, 5-bis-(methyl1)-2 ,3,4 ,5 -tetrahydro- 1 H- 1, 3 -IIN-(4 ,4,4-trifluorobutryl)-L- (2-thienyl) g Iyc ine] -amino-2 ,4- d ioxo- 1, 5-bis-(cyclopropylImethyl)-2 ,3.4 ,5 etrahydro- I1H- 1,5 AS-4 benzodiazepine 0 861 4 4 ,4-trifluorobutryl)-L-(3-thienyl)glycine]-amino-2 4- dioxo- 1 .5-bis-(2-methylpropyl)-2 5-tetrahydro- 1H- 1 ,5-benzodi azepine 3- ,4 ,4-trifluorobury)-L-(3-thienyl)glycine] -amino-2 ,4- dioxo- 1 .5-bis-(methyl)-2 ,3 ,4,5-tetrahydro- I1H- 1 4 4 ,4-trifluorobutryl)-L-(3-thienyl)glycine]-amino-2,4- dioxo- 1 ,5-bis-(cyclopropylmethyI)-2 ,3 ,4,5-tetrahydro-1H- -benzodiazepine 4 ,4,4-trifluorobutryl)-L-cyclohexylglycinyl] -amino-2,4- dioxo- 1 .5-bis-(2-methylpropyl)-2 ,3,4 ,5-tetrahydro- 1H1-ii,5-benzodiazepine 3- ,4 4 -trifluorobutr-yl)-L-cyclohexylglyc inyl]-amino-2 .4- -dioxo- 1,5-bis-(methyl)-2 ,3 .4,5-tetrahydro- 1 H-1, 3 4 ,4,4-trifluorobutryl)-L-cyclohexylglycinyl]pamino-2 4- dioxo- 1 ,5-bi,-(cyclopropylmethyl)-2 3,4,5-tetrahydro- 1 H- -benzodiazepine ,4-trifluorobutryl)-L-threoninyl]-amnino-2 ,4-dioxo- bis-(2-methylpropyl)-2 5-tetrahydro- 1 H-i 03- ,4 ,4-trifluorobutryl)-threoninyl] -amino-2 ,4-dioxo- 1 o.o 25 bis-(methyl)-2 5-tetrahydro- 1 H-i1, 5 -benzodiazepine 3- ,4 ,4-trifluorobutryl)-L-threoninyl] -amino-2 ,4-dioxo- bis-(cyclopropylmethyl)-2 5-tetrahydro-l1H-i, 3-(3 ,5-difluorophenylacetyl)amino-2 ,3-dihydro-l1-methyl-5-phenyl-l1H- 1,4- benzodiazepin-2-one 03-(N ,5-difluorophenylacetyl)-L-alaninyl)axnino-2 ,3-dihydro-l1-ethyl-5- 0 0* phnlH- 1,4-benzodiazepin-2-one oo pey 35 5-difluorophenylacetyl)-L-alaninyl] -amino-2 ,3-dihydro-5-phenyl 00.0 1 H-1,4-benzodiazepin-2-one :o.o ,5-difluorophenylacetyl)-L-alaninyl] -amino-2 .3-dihydro-l1-methyl-S- (1 -piperidinyl)-l1H-i ,4-benzodiazepin-2-one 3-[N ,5-difluorophenylacetyl)-L-alaninyl] -amino-7-chloro-2 ,3-dihydro- 1- methyl-5-phenyl-l1H-i ,4-benzodiazepin-2-one N' 5-difluorophenylacetyl)-L-alaninyl] -amino-7-bromo-2. 3-dihydro- 1- '~ntyl-5-(2-fluorophenyI )-l1H-i ,4-benzodiazepin-2-one 862 3-[N ,5-difluorophenylacetyl -methyl-L-alaninyl)-amino-2 3-dihydro- 1 -methyl-5-phenyl- 1 H- 1,4-benzodiazepin-2-one 3-[N .5-difluorophenylacetyl)-L-alaninyl] -amino-7-chloro-2 ,3-dihydro- 1 methyl-5-(2-chlorophenyl)- 1 H-i ,4-benzodiazepin-2-one 3-[N .5-difluorophenylaceryI)-L-alaninyIJ-amino-5-cyclohexy-2 3- dihydro- 1 -methyl- I H-1, 4-benzodiazepin-2-one 3-[N 5-difluorophenylacetyl)-L-alaninyl] -amino-2 .3-dihydro- 1 -methyl-7- 1H- 1, 4-benzod iazepin-2 -one 3-[N ,5-difluorophenylacetyl)-L-alaninyl] -amino-2 .3-dihydro- 1 (2-fluorophenyl)- IH- 1,4-benzodiazepin-2 -one 3-[N '-(3,5dfurpey-c-yrxaey)L-aiy]aio23-dihydro- I methyl-5-phenyl-1H- 1 ,4-benzodiazepin-2-one 3- .5-difluorophenyl-ce-hydroxyacetyI)-L-ten-leuciny 1] -amino-2 ,3- dihydro- 1 -methyl-5-phenyl- 1 H-i 14-benzodiazepin-2-one 3 (3 ,5-difluoropheny lacetyl)-L-al aninylI] -amino-2, 3-d ihydro- 1 -methy1- 5 -fluorophenyl1)- 1H-1, ,4-benzod iazepin-2 -one 3[N' ,5-difluorophenylacetylI)-L-al aniny1) amino-2 ,3 -dihydro- 1 -methyl-5 (4-fluorophenyl)- I H-i ,4-benzodiazep in-2-one -(cyclopentyl-cr-hydroxyacetyl)-L-alaninyl]-amino-2,3-dihydro- 1- methyl-5-phenyl-l1H-i ,4-benzodiazepin-2-one 3-[N '-(cyclopentyl-ce-hydroxyacetyl)-L-valinyl]-amino-2 ,3-dihydro- 1- 1H- 1, 4-benzodiazepin- 2-one 3 ,5 -difluoropheny lacetyl) -L-al aniny I]amino-2,3 3-d ihydro- 1,5 dimnethyl- 1 H- 1 ,4-benzodiazepin-2-one ,5-difluorophenylacetyl)-L-alaninyl] amino-2 ,3-dihydro-l1-isobutyl-5- phenyl)- 1H- 1,4-benzodiazepin-2-one 3- difluorophenyl-ca-hydroxyacetyl)-L-alaninyl] amino-2.3-dihydro- 1 -methyl-5 -phenyl- 1 H- 1 ,4-benzodiazepin-2-one 3-[N S-difluorophenyl-cx-oxoacetyl)-L-alaninyllamino-2, 3-dihvdro- 1 methyl-5-phenyl-1H- 1,4-benzodiazepin-2-one 3- 2 -methylthioacetyl)-L-alaninyl]amino-2, 3-dihydro- 1 1 H- 1,4-benzodiazepin-2-one 863 5-difluorophenylacetyl)-L-valinyl]amino-2, 3-dihydro- 1 phenyl- 1H- 1 ,4-benzodiazepin-2-one 3- [N (3 5-difluoropheny lacetyl)-L-tert- leuc inyI Iarnino- 2,3 -dihydro- 1 methyl-5-phenyl- 11- 1, 4-benzodiazepin-2 -one 3 ,5 -difluorophenylacetyl) -L-alaninyl1]amino- 2,3 -dihydro- 1 -isopropyl- 5-phenyl-1H-1 ,4-benzodiazepin-2-one 3- [N ,5-difluorophenylacetyl)-L-alaninyl] amino-2 .3-dihydro- 1 1H-i 1,4-benzodiazepin-2 -one 3-[N ,5-difluorophenyl-ce-fluoroacetyl)-L-alaninyIJamino-2 ,3-dihydro- 1 1 H-i ,4-benzodiazepin-2-one 3-[N .5-difluorophenylacetyl)-L-alaninyl]amino-2, 3-dihydro- 1 -n-propyl- 1 H-i ,4-benzodiazepin-2-one -(3-methylbutyryl)-L-phenylglycinyl]amino-2 ,3-dihydro- 1 phenyl-l1H-i ,4-benzodiazepin-2-one 3- ,5-difluorophenylacetyl)-L-phenylglycinyl] amino-2,3dhdo 1 1 H-i 1,4-benzod iazepin-2 -one 3- [N '-(2-phenylthioacetyl)-L-alaninyl] arino-2 ,3-dihydro-l1-methyl-5-phenyl- 1 H-i, 4-benzodiazepin-2-one 3- -(3-methylbutyryl)-L-alaninyljamino-2 ,3 1H- 1,4-berizodiazepin-2-one 3- -(2-phenylthioacetyl)-L-phenylglycinyl] amino-2,3-dihydro- 1-methyl-S pheiy-1- 3 [N-(3-(4-methoxyphenyl)propionyl)-L-alaninylI amino-2, 3-dihydro- 1 35methyl-5-phenyl-l1H-i ,4-benzodiazepin-2-one 3- -(3-bromophenylacetyl)-L-alaninyl] amino-2, 3-dihydro- 1 phenyl-1H- 1,4-benzodiazepin-2-one 3- -(4-cyclohexylbutyryl)-L-alaninyl] amino-2 ,3-dihydro- i-methyl-S phenyl- 1H- 1 ,4-benzodiazepin-2-one 3-[N '-(4-methoxyphenylacetyl)-L-alaninyl] amino-2 ,3-dihydro- 1 -methyl-5-(2- pyridyl1)-i H-i ,4-benzodiazepin-2-one 3 -(3-methyl-2-hydroxylbutyryl)-L-alaninyl]amino-2 .3-dihydro- 1 -methyl- /SF 5-phenyl- IH- 1.4-benzodiazepin-2-one 864 3-[N '-(3-methyI-2-hydroxylbutyry)-L-aaninyI]amino-2,3-dihydro- I -merthy I1- 5-phenyl-1IH-1, ,4-benzodiazepin-2 -one 3-[N ,3-dinlethylbutyryl)-L-alaninyllamino-2,3-dihydro- 1 phenyl- 1H- 1 ,4-benzodiazepin-2-one 3-[N '-(thien- 2 -yl-acetyl)-L-alaninyljaxnino-2 ,3-dihydro- 1 -methyl-5-(2- pyridy I H-i ,4-benzodiazepin-2-one 3-[N .5-difluorophenylacetyl)-L-alaninyl] amino-2 ,3-dihydro- I (2-pyridyl)-1H- 1 ,4-benzodiazepin-2-one 3- 3 -bromophenylacetyl)-L-alaninyl] amino-2 ,3-dihydro- 1 -methyl pyridy 1)-i1 H-i ,4-benzodiazepin-2-one 3- 2 -phenylthioacetylI)-L-alaninylI]arnino-2,3 3-dihydro- 1 -methyl-5-(2- pyridyl)-1H-1 ,4-benzodiazepin-2-one 3-[N 4 -ethoxyphenylacetyl)-L-alaninyljamino-2 ,3-dihydro- 1 -methyl-5-(2- pyridyl)- 1 H-i ,4-benzodiazepin-2-one 3- 4 -trifluoromethylphenylacety l)-L-alaninyl) amino-2 ,3-dihydro- 1 methyl-5-(2-pyridyl)- 1 H-i 1, 4 -benzodiazepin-2 -one :000 25 3- [N ,-di(trifluoromethyl)pheny acety)LalaIiny] in-2 3-d ihvdro- 1 methyl-5-(2-pyridyl)- IH-1, 4 -benzodiazepin-2 -one Soo 0 3- [N 2 -methylthioacetyl)-L-alaninyl] amino-2, 3-dihydro- 1 -methyl-5-(2- pyridyl)- 1H- 1 4 -benzodiazepin-2-one 3- 2 -cyclohexylacetyl)-L-alaninyl]arnino- 2,3-dihyd ro- 1 -methyl-5 pyridyl)-i1H- 1,4-berizodiazepin-2-one 3 -S 3[N 6 -pentafluoropheny loxyacety I)L-alaniny 1]arino- 2,3 3-d ihydro- 1 -methyl-5-(2-pyridyl)- 1 H-i 4 -benzodiazepin-2-one 3-[N '-(thionaphth-3-ylacetyl)-L-alaninyi]amino-2, 3-dihydro-l1-methyl-5-(2- pyridyl)-l11-1 4 -benzodiazepin-2-one 3- [N 6-trimethylphenylacetyl)iLalaninyl] amino-2 ,3-dihydro- 1-methyvl- 5-(2-pyridyl)- 1H-i 4 -benzodiazepin-2-one 3-[N '-((4-phenyl)phenylacety)-L-aaniny1]mino-2 ,3-dihydro- 1-methvl-5-(2- pyridyl)- 1H-i 4 -berzodiazepin-2-one S3-[N' ,4-difluorophenylacetyl)-L-alaninyl] amino-2.,3-dihydro-lI-methyl-5- SA. (2-pyridyl)- 1H-i 4 -benzodiazepin-2-one 865 3- -(4-(thien-2-y l)buryry1) -L-alaninyl]arnino-2. 3-dihydro- 1 -methyl-5-(2- pyridyl)- 1H-1, ,4-benzodiazepin-2 -one 3-[N '-(5-niethylhexanoyl)-L-alaninyl~ainino-2, 3-dihydro- 1 -methyl-5-(2- pyridyl)- 1H-i ,4-benzodiazepin-2-one 3- [N '-(2-methoxycarbonylacetyl)-L-alaninyljamino-2, 3-dihydro- 1 (2-pyridyl)- 1 H-i ,4-benzodiazepin-2-one 3- 6-difluorophenyl)-ce-hydroxyacetyl)-L-alaninyl] amino-2 ,3-dihydro-. 1 -methyl-5-(2-pyridyl)- 1 H-i ,4-benzodiazepin-2-one 3-[N '-(4-fluorophenyl)-ce-hydroxyacetyl)-L-alaninyllamino-2 ,3-dihydro- 1 methyl-5-(2-pyridyl)- 1 H-i ,4-benzodiazepin-2-one 3- 5-difluorophenyl)-a-hydroxyacetyI)-L-alaninyl]amino-2.3 -dihydro- 1 -methyl-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3- 6-trifluorophenyl)acetyl)-L-alaninyl] amino-2, 3-dihydro- 1 -methyl 5-(2-pyridyl)- 1 H-i ,4-benzodiazepin-2-one 3- -(2-trifluoromethyl-4-fluorophenyl)acetyl)-L-alaniny l~amino-2, 3- dihydro- 1 -methyl-5-(2-pyridyl)- 1 H-i ,4-benzodiazepin-2-one 25 3-[N'-(4,4,4-trifluorobutyryl)-L-alaninyl]amino-2 ,3-dihydro- 1 -methy 1-5-(2- pyridyl)- 1H-i ,4-benzodiazepin-2-one 3-[N '-(4-iso-propylphenylacetyl)-L-alaninyl] amino-2 ,3-dihydro- 1-methyl-S (2-pyridyl)- iH- 1,4-benzodiazepin-2-one 3-[N '-(3-phenyl-2-hydroxypropionyl)-L-alaninyl]amino-2 ,3-dihydro- 1- methyl-5-(2-pyridyl)-l1H-i ,4-benzod iazepin-2-one '-(phenyl-cr-hydroxyacetyl)-L-alaninyl] amino-2 ,3-dihydro-l1-methyl-5- (2-pyridyl)- 1H- 1 ,4-benzodiazepin-2-one 3- [N '-(4-chlorophenyl-cx-hydroxyacety I)-L-alaninyl] amino- 2,3 -dihydro- 1- methyl-5-(2-pyridyl)- 1H-1I,4-benzodiazepin-2-one -(3-methylbutyryl)-L-alaninyl] amino-2 ,3-dihydro- 1 -methyl-5-(2- pyridy LH- 1, 4-benzodiazepin-2-one 3-[N ,5-trifluorophenylacetyl)-L-alaninyl] amino-2 ,3-dihydro- 1 -methylI- 5-(2-pyridyl)- 1H-i ,4-benzodiazepin-2-one 18- 3-[N'-(3-methylthiopropionyl)-L-alaninyl]amino-2,3-dihydro. 1-methyl-5-(2- _pyridyl)-1H-1 ,4-benzodiazepin-2-one 866 3-[N 3 -methyl-2-hydroxybutyryl)-L-alaninyljamino-2, 3-dihydro- I1-methyl- 5-(2-pyridyl)- 1H- 1 ,4-benzodiazepin-2-one 3-[N '-(3-nitrophenylacetyl)-L-alaninyllamino-2 ,3-dihydro- 1 -methyl-5-(2- pyridyl)- 1H-1 ,4-benzodiazepin-2-one 3-[N '-(4-methoxyphenylacetyl)-L-alaninyl] amino-2 ,3-dihydro- 1 -(tenT- butylcarbonylmethyl)-5-(2-pyridyl)-lH- 1 ,4-benzodiazepin-2-one 3-[N '-(2-thienylacetyl)-L-alaninyllamino-2, 3-dihydro- 1 -(te/7- butylcarbonylmethyl)-5-(2-pyridyl)- 1 H-i ,4-benzodiazepin-2-one 3-[N ,5-difluorophenylacetyl)-L-alariinyl~amino-2,3-dihydro- 1 -(tenl- butylcarbonylmethy1)-5-(2-pyridy])- 1Hi 1,4-benzodiazepin-2-one 3-[N '-(3-bromophenylacetyl)-L-alaninyl]amino-2 .3-dihydro- 1 -(tenT- butylcarbonylmethyl)-5-(2-pyridyl)- 1 H-1, 4-benzodiazepin-2-one 3- -(2-phenylthioacetyl)-L-alaninyl] amino-2.3 -dihydro- 1 -(tent- butylcarbonylmethyl)-5-(2-pyridyl)- 1 H-1, 4-benzodiazepin-2-one 3- -(4-ethoxyphenylacetyl)-L-alaninyl) amino-2 ,3-dihydro- 1 -(ten7- butylcarbonylmethyl)-5-(2-pyridyl)- 1 H-i 1,4-benzodiazepin-2-one 3-[N '-(4-trifluorornethylphenylacetyl)-L-alaninyl] amino-2 ,3-dihydro- 1 -(tent- butylcarbonylmethyl)-5-(2-pyridyl)- 1H- 1 ,4-benzodiazepin-2-one 3-[N ,5-di-(trifluoromethyl)phenylacetyI)-L-alaniny1]amino-2.3-dihydro- 1 -(rn-butylcarbonylmethyl)-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3- -(2-methylthioacetyl)-L-alaninyl]amino-2 ,3 -dihydro-l1-(te-- butylcarbonylmethyl)-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3- [N '-(2-cyclomethylacetyl)-L-alaninyllamino-2 ,3-dihydro-l1-(tent- butylcarbonylniethyl)-5-(2-pyridyl)- 1 H-i ,4-benzodiazepin-2-one 3- 6 -pentafluoropheny loxyacetyI)-L-alaninyl) amino- 2,3-d ihydro 1 -(terr-butylcarbonylmethyl)-5-(2-pyriayl)-l1H-i, 4-benzodiazepin-2-one 3-[N '-(thionaphth-3-ylacetyl)-L-alaninyl]amino-2 ,3-dihydro-l1-(tent- -(2-pyridyl)- 1 H-1, 4-benzodiazepin-2-one 3-[N ,4,6-trimethylphenylacetyl)-L-alaninyllamino-2 ,3-dihydro- 1 -(tent- butylcarbonylmethyl)-5-(2-pyridyl)- 1H- ,4-benzodiazepin-2-one 867 3-[N '-((4-phenyl)phenylacetyl)-L-alaninyllamino-2 ,3-dihydro- I -(ten- burylcarbonylmethyl)-5-(2-pyridyl)- 1 H-i 1, 4 -benzodiazepin- 2-one 3-[N 4 -difluorophenylaceyl)-L-alaniny]amino-2 ,3-dihydro- 1 -(teri- butylcarbonylmethyl)-5 -(2-pyridyl)- 1 H-i 1, 4 -benzodiazepin-2 -one 3-[N 4 2 -thienyl)butyryl)-L-alaninyl] anino-2 ,3-dihydro- I -(Ienl- butylcarbonylmethyl)-5-(2-pyridyl)- 1 H-i 1,4-benzodiazep in-2 -one 3-[N '-(5-methylhexanoyl)-L-alaninyl] amino-2 ,3-dihydro- 1 -(tent- butylcarbonylmethyI)-5-(2-pyridyl)- 1 H-1, 4 -benzodiazepin-2-one 3- -(2-methoxycarbonyiacetyl)-L-alaninyl] amino-2 ,3-dihydro- 1 -(teri- butylcarbonylmethyl)-5-(2-pyridyl)1H.I H-, 4 -benzodiazepin-2-one 3- 6 -difluorophenyl-ce-hydroxyacety1)..L..aaninyl]amino-2 ,3-dihydro- 1 -(tent-butylcarbonylmethy)-5-(2-pyridyl) 1 H-i 1, 4-benzodiazepin-2 -one 3-[N 4 -fluoropheny-ci-hydroxyacety)-L.alaninyl] amino-2.3 -d ihvdro- 1- (ten-butylcarbonylmethyl)-5-(2-pyridyl). 1 H-i ,4-benzodiazepin-2-one 3- S-difluorophenyI-ce-hydroxyacetyl>L-aaninyl] amino-2 ,3-dihydro- 1 -(trn-butylcarbonylmethyl)-5 -pyridy 1 H 1,4-benzodiazepin-2 -one 3- [N 6 -trifluorophenylacetyl)-L-alaninyllamino-2, 3-dihydro- 1 -(tent- butylcarbonylmethyl)-5-(2-pyridyl). 1 H-i1, 4 -benzodiazepin-2-one 3-[N 2 -trifluoromethyl-4-fluorophenyacety)Laaninvl] amino-2 .3- -(2-pyridyl)- 1H-i ,4-benzodiazepin-2- one 3-[N 4 -trifluorobutyryl)-L-alaninyl] amino-2 ,3-dihydro-lI-(tern- buty lcarbonylmethyl)-5-(2-pyridyl)-l1H-i 4 -benzodiazepin-2-one 35 3- [N 4 -iso-propylphenylacetyl)-L-alaninyl)amino-2, 3-dihydro- 1 -(tert- butylcarbonylmethyl)-5-(2-pyridyl)- 1 H-i 1, 4 -benzodiazepin-2-one 3 3 -phenyl-2-hydroxypropionyl>L..alaniny I]-mino.23dihydro- 1 -(tent- butylcarbonylmethyl)-5-(2-pyridyl). 1 H-i 4 -benzodiazepin-2-one 3 [N'-(phenyl-ce-hydroxyacety)Laaniny1Iaino-2, 3-dihydro- 1 -(tent- butylcarbonyimethy1)-5-(2-pyridy 1)-i1 H-i 4 -benzodiazepin-2-one 3-[N 4 -chlorophenylacetyl)-L-alaninyl] amino-2 ,3-dihydro- 1 -(zent- butylcarbonylrnethyl)-5-(2-pyridyl). 1H-i 4 -benzodiazepin-2-one 868 3-[N 3 -methylbutyryl)-L-alaninyljamino.2,3-dihydro- 1 -(tert- butylcarbonylmethyl)-5-(2-pyridyly- 1 H-i 1, 4 benzodiazepin-2 -one 3-[N ,-trifluorophenylacetyI)-L-alaninyl]amin-2 ,3-dihydro-l1-(tent- burylcarbonylmethyl)-5-(2-pyridyl 1 H-i1, 4 -benzodiazepin-2 -one 3 3 -methylthiopropionyl)-L-alaninylamino.2 3-dihydro- 1 -(ten7- butylcarbonylmethyl)-5-(2-pyridyl)- 1 H-i 1, 4-benzod iazepin-2 -one 3 -methyl-2-hydroxybutyIy)-L-alaninyl~jamino-2,3-dihydro- 1 -(zert- butylcarbonylmethy)5(2-pyridy))lH-1 4 -benzodiazepin-2-one 3 3 -nirophenylacey)-L-alaniny]amino-2, 3-dihydro- I -(tenT- butylcarbonylmethy1)-5-(2-pyridyI)- 1 H-1, 4 -benzodiazepin-2 -one 3-[N 4 -methoxyphenylacetyI)-L-alaniny]amino23-dihydro- 1 N- diethylamino)ethyl)-5-(2-pyridyl)- 1 H-i1, 4 -benzodiazepin-2 -one 3- 2 -thienylacetyl)-L-alaninyllamino-2 ,3-dihydro-1 N- diethylamino)ethyI1) -5 -pyridy I)>1 H-i 1, 4 -benzodiazep in-2 -one 3-[N ,5-difluorophenylacetyl)-L-alaninyl] amino-2 ,3-dihydro- 1 ,N- diethylaxnino)ethyl)-5-(2-pyridyl). 1 H-i 4 -benzodiazepin-2-one 3 [N'-(3-bromopheny lacety)-L-aaniny] ino-2, 3-dihydro- 1 (2 N- diethy lamino)ethyl)- 5-(2 -pyridy1)- 1 H-i 1, 4 -benzodiazepin-2-one 3-[N 2 -phenylthioacetyl)-L-alaninyl]amino.2 3-dihydro-l1-(2-(N ,N- -(2-pyridy). 1 H-i 1, 4 -benzodiazepin-2 -one 3-[N 4 -ethoxyphenylacetyl)-L-alaninyl] amino-2,3-dihydro-l1-(2-(N .N- diethylamino)ethyl)-5-(2 -pyridy)IH-1, ,4-benzod iazepin- 2-one 3- 2 -methylthioacetyl)-L-alaninyl] amino-2 ,3-dihydro-l1-(2-(N ,N- diethylamino)ethyl)-5-(2-pyridy1)- 1 H 1,4-benzod iazepin-2-one 3-[N 2 -cyclohexylacetyl)-L-alaninyljamino-2,3-dihydro- 1 N- diethylamino)ethyl)-5-(2-pyridyl). 1 H-i 4 -benzodiazepin-2-one *40 6 -pentafluorophenyloxyacetylL-alaninylamino-2, 3-dihydro- 1 ,N-diethylamino)ethyl)-5-(2-pyridyl1)-i H-i 1, 4 -benzodiazepin-2 -one 3 2 -thionaphth3yacety).L.alaninyljamino.2 ,3-dihydro- 1 ,N diethylamino)ethyI)-5-(2-pyridy1). 1H 1 ,4-benzodiazepin-2-one 3 2 -phenyI-2-oxoacetyl)yL-alaninyl]amino-2 .3-dihydro- 1 N- diethylamino)ethyl)-5-(2-pyridyl>- 1 H-i .4-benzodiazepin-2-one 869 3-[N ,6-trimethylphenylacetyl)-L-alaninyllamino-2 ,3-dihydro- 1 (N ,N-diethylamino)ethyl)-5-(2-pyridyl)- I H-i 1,4-benzodiazepin-2 -one -((4-phenyl)phenylacetyl)-L-alaninyl]amino-2,3-dihydro- 1 ,N- diethylaniino)ethyl)-5-(2-pyridyl)- 1H-i 1,4-benzodiazepin-2 -one .4-difluorophenyl)acetyl)-L-alaninyljaniino-2 ,3-dihydro- 1 ,N- diethylamino)ethyl)-5-(2-pyridyl)- 1 H-i 1,4-benzodiazepin-2 -one 3-[N '-((4-(thien-2-yl)butyryl)-L-alaninyl~amino-2 .3-dihydro- N- diethylamino)ethyl)-5-(2-pyridyl)- 1 H-i1, 4-benzod iazepin-2 -one 3- -(5-methylhexanoylI)-L-alaniny 1] amino-2,3 3-dihydro- 1 ,N- diethylaxnino)ethyl)-5-(2-pyridyl)- 1 H-1, 4-benzodiazepin-2-one -(2-methoxycarbonylacetyl)-L-alaninyl] amino-2 ,3-dihydro- 1- (2 N- diethylaxnino)ethy 1)-5-(2-pyridyl)- 1 H-1, 4-benzodiazepin-2-one ,6-difluoropheny-ce-hydroxyacety)-L-alaninyl}amino-2, 3-dihydro- 1 ,N-diethylamino)ethyl)-5-(2-pyridyl)- 1 H-i 1,4-benzodiazep in-2 -one 3- -(4-fluoropheniyl-ce-hydroxyacetyl)-L-alaninyl] amino-2, 3-dihydro- 1 (N ,N-diethylamino)ethyl)-5-(2-pyridyl)- 1 H-i 1,4-benzodiazepin-2 -one 3-[N ,5-difluorophenyl-ca-hydroxyacetyl)-L-alaninyl~amino-2 ,3 -dihydro- N-diethylamino)ethyl)-5 -(2-pyridy 1 H-i 1,4-benzodiazepin-2-one 3-[N '-(4-hydroxymethylphenyloxyacetyl)-L-alaninyl]amino-2 ,3-dihydro- 1- ,N-diethylamino)ethyl)-5-(2-pyridyl)-l1H-i .4-benzodiazepin-2-one 3- [N ,6-trifluorophenylacetyl)-L-alaninyllamino-2 ,3-dihydro- 1 N-diethylamino)ethyl)-5-(2-pyridyl)- 1 H 1,4-benzodiazepin-2- one 3- -(2-trifluoromethyl-4-fluorophenylacetyl)-L-alaninyl] amino-2, 3- dihydro-1-(2-(N ,N-diethylamino)ethyl)-5-(2-pyridyl)- iH-i ,4-benzodiazepin- 2-one 3-[N '-(4,4,4-trifluorobutyryl)-L-alaniny1] amino-2 3-dihydro- 1- (2 N diethylamino)ethyl)-5-(2-pyridyl)-l1H-i ,4-benzodiazepin-2-one 3- [N'-(4-iso-propy lpheny lacety1) -L-alaniny I ]arnino-2,3 3-dihydro- 1- (2 N diethy larnino)ethylI)-5-(2-pyridyl1)- 1 H-i 1,4-benzod iazepin-2-one 3- -(3-phenyl-2-hydroxypropionyl)-L-alaninyl) amino-2 ,3-dihydro-l1-(2- 4) (N ,N-diethylamino)ethyl)-5-(2-pyridyl)-l1H-i .4-benzodiazepin-2-one 8'70 3-[N '-(phenyl-cehydroxyacetyl)-L-alaninyljamino-2 ,3-dihydro- 1 N- diethylamino)ethyl)-5-(2-pyridyl 1 H-i 4 -benzodiazepin-2-one 3- 4 -chlorophenyi-ot-hydroxyacetyl)-L-alaninyllamo.23-dihydro- 1 (N ,N-diethylarnino)ethyl)-5-(2-pyridyl)- 1 H-i 1.4-benzodiazepin-2 -one 3-[N .5-difluoropheny1-a-hydroxyacey)-L-3-thienylglycinyllamjno-2 .4- dioxo- 1 ,-bis(2,2-dimethypropy)2,3,4,5tetrahydro H 1 benzodiazepine 3-[N S-difluorophenyl-ce-hydroxyacetyl)-L-alaninylI]amino-2 .4-dioxo- 1 phenyl-5-methyl-2 .3 4,5-tetrahydro- 1 H-i 3- ,5-difluoropheny1-ce-hydroxyacetyI)-L-alaninyijamino.2-oxo-l-1 methyl-5-phenyl- 1,3,4 ,5-tetrahydro- 1 H-i 3-[N ,5-difluorophenylacetyl)-L-alaninyllamini-L.IH-imidazole[ 1,2-a] -6- phenyl- 1,4-benzodiazepine 4-[N ,5-difluorophenylacetyl)-L-alaninyllaino-L- IH-imidazole[ 1,2-a] 2 ,4-dihydro-6-phenyl- 1 ,4-benzodiazepine 4- 5-difluorophenylacetyl)-L-alaninyl] amino-L-4H 1 triazole [4,3 a] -6-phenyl- 1 ,4-benzodiazepine 3-[N ,5-difluorophenylacetyl)-L-alaninyllamino-2 ,4-dioxo- 1 ,5-bis-( 1- methylethyl)-2, 3,4,5-tetrahydro-l1H-i, ,5-difluorophenylacetyl).-(R)-2-thienylglycinyljamino.2 ,4-dioxo- bis-(l1-methylethyl)-2 ,3 .4,5-tetrahydro-1H- 1, 3- -(cyclopropylacetyl)-R-2-thienylglyciny 1] axino-2 ,4-dioxo- 1,5-bis-( 1- methylethyl)-2 .3,4 .5-tetrahydro-l1H-i, 3-[N '-(cyclopentylacetyl)-R-2-thienylglycinyl] axnino-2 ,4-dioxo- 1, 5-bis-( 1- methylethyl)-2 5-tetrahydro- 1 H-1, 3- [N ,5-difluorophenylacetyl)-L-alaninyl] amino-2 ,4-dioxo- 1, 2,3,4,5-tetrahydro-l1H-i 3- ,5-difluoropheny I-a-hydroxyacety1)-L-alaniny1] amino-2 ,4-dioxo- 1, bis-methyl-2, 3,4 ,5-tetrahydro- 1H- 1, 3- ,5-difluorophenylacetyl)-L-alaninyl] amino-2 ,4-d ioxo- 1, 5-bis-(2 methylpropyl)-2 5-tetrahydro- 1 H-i1, 871 3-[N'-(cyclopentylacetyl)-L-alaninyl] amino-2 ,4-d joxo- 1 ,5-bis-(2- methylpropyl)-2 5-tetrahydro- 1 H-i 1, 3-[N '-(cyclopropylacetyI)-L-alaninyIJ-amino-2 4-dioxo- 1 ,5-bis-(2- methylpropyl)-2.3 ,4,5-tetrahydro- 1 H-i ,S-benzodiazepine 3-[N .S-difluorophenylacetyl)-S-2-phenylglycinylp-amino-2 4-dioxo- bis-(2-methylpropyl)-2 5-tetrahydro- 1 H-i 3-[N 5-difluorophenylacetyl)-L-alaninyl]-amino-2,4-dioxo- 1 ,S-bis- (cyclopropylmethyl)-2 5-tetrahydro- 1 H-1, 3-(N '-(cyclopentylacetyl)-L-alaninyll-amino-2,4-dioxo- 1 (cyclopropylmethyl)-2 ,3,4,5 -tetrahydro- 1 H- 1, 3-[N '-(cyclopentyl-ce-hydroxyacey)-L-ala11jnyl]..amin-2 ,4-d joxo- 1, (cyclopropylmethyl)-2 5-tetrahydro- 1 H-i 3-[N ,S-difluorophenylacetyl)-L-alaninyl]-amino-2,4-dioxo- 1. 5-bis-(2 .2- dimethylpropyl)-2 5-tetrahydro- 1 H-i 3 S-difluoropheny1 -a-hydroxyacety I)-L-alaniny 1] amino- 2,4-d ioxo- 1 ,5-bis-(2 ,2-dimethylpropyl);2 ,3 ,4 ,5-tetrahydro- 1 H-i 3-[N '-(cyclopentylacetyl)-L-alaninyllamino-2 ,4-dioxo- 1 ,5-bis-(2 .2- dimethy lpropylI)-2.3 ,4,5-tetrahydro- 1 H- 1, 5-benzodiazep ine 3-[N '-(cyclopentyl-a-hydroxyacetyl)-L-alaninyl] amino-2 ,4-dioxo- 1, 5 -bis- (2 ,2-dimethylpropyl)-2,3 ,4,5-tetrahydro- 1 H- 1,5 -benzodiazepine 30 3-[N ,5-difluorophenylacetyl)-L-alaninyl]-amino.2 ,4-dioxo- 1, phenyl-2 ,3 ,4,5-tetrahydro-l1H-i 3-[N '-(cyclopentylacetyl)-L-alaninyljamino-2 ,4-dioxo- 5-bis-pheny 1- 2,3,4,5-tetrahydro-i.H-1 3- -(cyclopentyl-c-hydroxyacetyh,-L- alaninyl] -amino-2 ,4-dioxo- 1 pheny1-2 ,3 ,4,5 -tetrahydro- 1 H- 1, 5 -benzodiazepine 40 3-(N ,5-difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-l1-methyl-5- phenyl-1H-1 ,4-benzodiazepin-2-one -(cyc lopenty lacety L-alaninyl1 }-amino- 7-methyl 5,7 -dihydro-6H dibenz~b azepin-6-one N' 3 -cyclopentylpropiony I)-L-alaniny 1) -amino-7-methyl-5 .7-dihydro- 6H-dibenz[b,djazepin-6-one -872 N '-(cyclohexy lacetyl)-L-alaninyl -amino- 7- methyI- 5, 7-d ihydro-6H- dibenz(b. dlazepin-6-one N'-(t-butylacetyl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro-6H- dibenz[b,djazepin-6-one '-(pheny lacetyI1)-L-aI~ninyI1) -amino- 7-methyl -5 ,7-dihydro-6H- dibenz(b,d]azepin-6-one 5-{N'-(3-bromophenylacey)-L-alaniny1 }-amino-7-methyl-5 ,7-dihydro-6H- dibenz[b,dllazepin-6-one -fluoropheny lacetylI)-L-alaninyl 1)-amino- 7-methy I- 5,7-dihyd ro-6H- dibenz[b ,d]azepin-6-one N'-(3-chlorophenylacetylv)-L-alaninyl)}-amino-7-methyl-5 ,7-dihydro-6H- dibenz[b,d]azepin-6-one N'-(3-(trifluoromethyl)khenylacetyl)-L-alaninyl} -amino-7-methyl-5 .7- dihydro-6H-dibenzb,dJ azlpin-6-one N'-(4-fluorophenylaceyl)-L-alaninyl)-arnino-7-methyl-5 ,7-.dihydro-6H- dibenz(b ,dlazepin-6-one 5- -(hexanoyl)-L-alaninl I}I-amino- 7-methyl-5 ,7-dihydro-6H- dibenz[b,d]azepin-6-one 5-{N'-(heptanoyl)-L-alanin'yl}-aniino-7-methyl-5 ,7-dihydro-6H- dibenb ,d~azepin-6-one 5-{3 ,4-difluorophenylacetyl)-L-alaninyl} -amino-7-methyl-5 ,7-dihydro-6H- dibeniz[b,djazepin-6-one -(cyclopropylacetyl)-L-alaninylI -amino-7-inethyl-5 ,7-dihydro-6H- dibenz[b,djazepin-6-one {N '-(2-cyclopentene- 1 -a Icetyl)- L-alaniinyl }-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b ,dlazepin-6-one 5-{N'-(3-cyclohexylpropi'nyl)-L-alaninyl}-aznino-7-methy-5 ,7-dihydro-6H- :dibenz[b~djazepin-6-one '-(isovateryl)-L-aaniiy-amino-7-methy1-5 ,7-dihydro-6H- dibenb ,dlazepin-6-one '-(citronellyl)-L-alaniinyl }-amino-7-methyl-5 ,7-dihydro-6- dibenz[b ,dI azepin-6-one -873 -benzoy lpropiony L-alaniny 1) -amino- 7-methyl-5 ,7 -d ihydro-6H dibenz[b ,dlazepin-6-one 5-f{N'-(2-chloropheny lacetylI)-L-alaninyl 1)-amino- 7-methyI- 5 ,7 -d ihydro-6H- dibenz[b,d]azepin-6-one N' -(4-pentenoyl)-L-aianinyl }-amino-7-methyl-5, 7-dihydro-6H- dibenz[b ,d]azepin-6-one 5-{N'-(valeryl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro-6H- dibenb azepin-6-one '-(2-thiophenecetyl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro-6H- dibenz[b ,d]azepin-6-one -(4-(2-thienyl)butyiyl)-L-alaninyl }-aniino-7-methyl-5 ,7-dihydro-6-- dibenz[b dazepin-6-one {N '-(4-(4-nitrophenyl)butyryl)-L-alaninyl)}-amino-7-methyl-5.7 -dihydro- 6H-dibenzfb ,d]azepin-6-one ,4-difluorophenylacetyl)-L-alaninyl }-amino-7-methyl-5 ,7-dihvdro- 6H-dibenz[b ,djazepin-6-one 5-{N '-(2,6-difluorophenylacetyl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b ,dlazepin-6-one -(4-isopropylphenylacetyl)-L-alaninyl)}-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b, d]azepin-6-one {N -adaniantaneacetyl)-L-alaninyl)}-amino-7-methyl-5 ,7-dihydro-6H- dibenz(b,d~azepin-6-one N'-(cyclohexanepentanoyl)-L-alaninyl }-amnino-7-methyl-5 ,7-dihydro-6H dibenz[b,d]azepin-6-one N'-((methylthio)acetyl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro-6H- dibenzfb,d] azepin-6-one 5-{N '-(2-thiophenepentanoyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro-6H- dibenz[b ,dlazepin-6-one "9 5-1{N '-(2-norbornaneacetyl)-L-alaninyl) -amino-7-methyl-5 ,7-dihydro-6H dibenz[b ,d]azepin-6-one ,5-difluorophenylacetyl)-4-ethylnorleucinyl }-amino-7-methyl-5 ,7- dihydro-6H-dibenz[b .d]azepin-6-one 874 N 5-difluorophenylacetyl)-4-methylnoreuciny) }-amino- 7-methyl-5 .7- dihydro-6H-dibenz[b ,dJ azepin-6-one .5-difluorophenylacetyl)-3-cyclopropylalaninyl) -amnino- 7-methy I- 5,7-dihydro-6H-dibenz[b,djazepin-6-one 5-difluorophenylacetyl)-4-cyclohexylhomoalaniny I I -amino-7- .7-dihydro-6H-dibenz~b ,djazepin-6-one 5- {N .5-difluoroph-enylacetyl)-6-fluoronoreucinyl} -amino-7-methyl-5 .7- dihydro-6H-dibenz[b,d] azepin-6-one ,5-difluorophenylacetylI)-4-methvlnorleucinyl -amino-7-methyl-5, 7- dihydro-6H-dibenb d] azepin-6-one N' -(cyclohexylacetyl)-4-ethylnorleucinyl }-amino-7-methyl-5 .7-dihvdro- 6H-dibenz[b,d~azepin-6-one '-(cyclopropylacetyl)-4-ethylnoreucinyl-amino7metliyls 7-dihydro- 6H-dibenz[b,d]azepin-6-one '-(isovalery I)-4-ethylInorleuc inyl} amino- 7-methy I-5 ,7-dihyvdro-6H- dibenz[b ,djazepin-6-one *.25 3 -(trifluoromethyl)phenylacetyl)-4-ethylnorleucinyl-amino7methyl- 5, 7-dihydro-6H-dibenz[b,d]azepin-6-one ,4-difluorophenylacety)-4-ethylnorleucinyl }-amino-7 -methyl- 7- dihydro-6H-dibenb d] azepin-6-one *30 N' ,4-difluorophenylacety)-4-ethylnorleucinyl)}-amino-7-methy 1-5,7- dihydro-6H-dibenz[b daz~pin-6-one N'-(3-fluorophenylacetyl)-4-methylnorleucinyl)}-amino-7-methy 1-5,7- dihydro-6H-dibenz(b azepin-6-one N' -(cyclopentylacetyl)-4-methylnorleucinyl)}-amino-7-methyl-5,7- dihydro-6H-dibenz~b azepin-6-one '-(cyclohexylacetyl)-4-methylnoreucinyl amino7methyl 7-dihydro- .6H-dibenb azepin-6-one '-(cyclopropylacetyl)-4-methylnorleucinyl-amino7methyls ,7- dihydro-6H-dibenb azepin-6-one- 2 -thiopheneacetyl)-4-methylnorleucinyl }-amino-7-methyl-5 ,7- dihydro-6H-diberiz[b, dlazepin-6-one 875 (N'-(isovalerylI)-4-methy lnorleuc inyl 1)-amino- 7-methyl-5 7-dihydro-6H- dibenz[b .djazepin-6-one 3 -(trifluoromethyl)phenylacety)4-methylnorleuciny -amino-7- methyl-S .7-dihydro-6H-dibenzb.d]azepin-6-one 4 -fluorophenylacetyl)-4-methylnorleucinyl) -aznino-7-methyl-5 ,7- dihydro-6H-dibenz[b,d] azepin-6-one 5- {N .4-difluorophenylacetyl)-4-methyinorleucinyI I}-amino-7-methyl-5 ,7- dihydro-6H-dibenzgb dazepin-6-one 4 -difluorophenylacetyl)-4-methylnorleucinyl }-amino-7-methyl-5,7- dihydro-6H-dibenzb,d] azepin-6-one 3 -fluorophenylacetyl)-4-cyc IohexyIhomoalani ny I}I-amino- 7-methy I- ,7-dihydro-6H-dibenz[b,d]azepin-6-one '-(cyclopentylacetyl)- 4 -cyclohexylhomoalaninyl-amino-7methyl-..57- dihydro-6H-dibenz[b azepin-6-one {N '-(cyclohexylacetylI)-4-cyclohexylhomoalaniny I I-amino-7-me thyI- 5 ,7 dihydro-6H-dibenzb,d] azepin-6-one 5-f{N' -(cyc lopropylaceryl)-4-cyclohexy lhomoalaninyl) }-amino- 7-methy1- 5, 7- dihydro-6f{-dibenz[b dazepin-6-one N' -(isovaleryl)-4-cyclohexylhomoalaninyl }-amino-7-methyl-5 ,7-dihydro- 6H-dibenzfb dazepin-6-one {N '-(4-fluorophenylacetyl)-4-cyclohexyhomoalaninyl)}-amino-7-methy 1- ,7-dihydro-6H-dibenz~b ,dlazepin-6-one ,4-difluorophenylacetyl)-4-cyclohexylhomoalaninyl }-amino-7- methyl-S ,7-dihydro-6H-dibenb azepin-6-one ,4-difluorophenylacetyl)-4-cyclohexylhomoalaniny1 I} -amino-7 methyl-S ,7-dihydro-6H-dibenz[b dlazepin-6-one 5- {N '-(3-fluorophenylacetyl)-6-fluoronorleucinyl}-amino7-methyls dihydro-6H-dibenz[b ,d]azepin-6-one 5-{N'-(cyclopentylacetyl)-6-fluoronorleucinyl-amino7methyl-5, 7-dihydro- 6H-dibenb ,djazepin-6-one -(cyclohexylacetyl)-6-fluoronorleuciny 1) -amino-7-methyl1-5 .7-dihydro- 6H-dibenb ,dlazepin-6-one 876 -(cyclopropylaceryI)-6-fluoronorieucinyI I -amnino- 7-methyl -5,7 7-dihydro- 6H-dibenz~b ,djazepin-6-one {N'-(isovaleryl)-6-fluoronorleucinyl -anlino-7-methyl- 7-dihydro-6H- dibenzb,djazepin-6-one 5-f{N'-(3-(trifluoromethyl)phenylacety l)-6-fluoronorleucinyI 1 -amino-7- ,7-dihydro-6H-dibeiz [b ,d]azepin-6-one 4 -fluorophenylaceryl)-6-fluoronoreucinyI-amino7methy-5.7- diliydro-6H-dibenzfb azepin-6-one 4 -difluorophenylacetyl)-6fluoronoreuciny)amino7.methy1-5 7- dihydro-6H-dibenz~b dazepin-6-one 5-f 4 -difluoropheny lacety flu oronorleuc iny 1) ami no-7 met 1 7 dihydro-6H-dibenz[b azepin-6-one 4 -methoxyphenylacetyl)-L-alaninyl}-amino..7.methyl-5,7-dihydro- 6H-dibenzllb,djazepin-6-one 3 4 -methoxyphenyl)prop ionylI)-L-alaniny 1)-amino-7- methyI-5 ,7 7- dihydro-6H-dibenb d] azepin-6-one 1 -naphthy lacety1) -L-alaniny 1)-amino- 7-methy 1-5. 7-d ihydro-6H dibenz~b ,d]azepin-6-one 4 -methylenedioxyphenylacety1)-Laaniny1amino7methyls ,7- 30 dihydro-6H-dibenzfb azepin-6-one N' -(hydrocinnamyl)-L-alaninyl }-amino-7-methy]-5 ,7-dihydro-6H- dibenz[b dlazep in-6-one N '-(octanoyl)-L-alaninyl}-amino-7-rnethyl-5 ,7-dihydro-6H- dibenz[b,d~azepin-6-one S-{N'-(3-(3-hdrophenyl)propiony1)-L-alaninyl}-amino-7..methy1.5- dihydro-6H-dibenz[b azepin-6-one 3 4 mypheny 1)proiony)-L-aaniny}-amino-7mety1-5,7-diyr-H ~~~dihyn~dro6-ienbazepin-6-one 877 3 4 -hydroxyphenyl)propionyl)- L-alaninyl -aniino-7- methy 1-5 .7- dihydro-6H-dibenz[b d] azepin-6-one 5-trifluorophenylacetyl)-L-alaninyl }-amino-7-methyl-5 .7- dihydro-6H-dibenzb. dllazepini-6-one 5-{N'-(4-(4-methoxypheny)butri)-L-alaniny1}aino-7mey.5 7- dihydro-6H-dibenz~b, d] azepin-6-one 3 -(methoxycarbonyl)propiony1)-L-alaniny1}-amino7methy15 .7- dihydro-6H-dibenz~b ,d]azepin-6-one -(4-phenylbutyryl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro-6H- dibenb ,dljazepin-6-one -(3-(benzylthio)-propionyl)-L-alaninyl) -arnino-7 -methyl-5 ,7-dihydro- 6H--dibenz[b azepin-6-.one 3 -methy lpentanoyl)- L-alaninyI}I- arnino-7..methyl 7-d ihydro-6H dibenz~b,d]azepin-6-one 5-{(N'-(7-carbomethoxyheptanoyl)-L-alaniny I I-amino-7-methyl -5 ,7-dihydro- 6H-dibenz~b ,d]azepin-6-one 5-f{N'-(2-indanylacetyl)-L-alaninyl} -aniino-7-methyl-5 ,7-dihydro-6H- dibenz[b, d] azepin-6-one '-(5-carbomethoxypentanoyl)-L-alaniny 1) -amino- 7-methyI- 5,7 7-d ihydro- 6H-dibenz[b,d] azepin-6-one '-(2-methyl-3-Benzofuranacety 1)-L-alaninyl}-arnino-7-methyl-5 .7 dihydro-6H-dibenz[b azepin-6-one '-(propionyl)-L-alaninyl }-amino-7-metbyl-5 ,7-dihydro-6H- dibenz[b,d~azepin-6-one S5-{N'-(3-methoxypropiony)-L-alaniny1}-amino-7-methyl.5 ,7-dihydro-6H- dibenz[b ,d~azepin-6-one 40 5- {N '-(3-(4-fluoropheny I)propionyl)-L-alaninyl }-amino-7-methyl-5 ,7- dihydro-6H-dibenz[b ,d]azepin-6-one N -penterioyl)- L-alaninyl I} -arnino-7-methyl-5 7-dihydro-6H- dibenz[b,dljazepin-6-one 878 ,4-dichlorophenoxy)butyryl)-L-alaninyi }-amino-7-methyl-5 ,7- dihydro-6H-dibenz(b azepin-6-one N' 3-dichlorophenoxyacetyl)-L-alaninyl -amino.7.methyl.I 7-dihydro- 6H-dibenzb,dlazepin-6-one N'-(3-(4-chlorobenzoyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7- dihydro-6H-dibenzb, dlazepin-6-one 5- {N'-(4'-fluorosuccinanilyl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro-6H- dibenz[b ,d]azepin-6-one }-amnino-7-methyl-5, 7- dihydro-6H-dibenzb dazepin-6-one '-(2-fluoropheny lacety I)-L-alaninyl1) -am ino-7 -me thyl1-5, 7-dihydTO- 6H dibenz[b azepin-6-one '-(succinanilyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro-6H- dibenb ,dlazepin-6-one N' ,4-dichlorophenoxyacey1)-L-alaninyl}-aniino-7-methy1-5 .7-dihydro- 6H-dibenz[b ,d]azepin-6-one N' -(2-nitrophenylacetyl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro-6H dibenb d]azepin-6-one {N '-(beta-propylhydrocinnamyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b azepin-6-one 5-{N'-(3-(2,4-dimethylbenzoy)propiony)-L-alaninyl} -amino-7-methyl-5,2- 35 dihydro-6H-dibenzlb,dlazepin-6-one 5-f{N'-(2-fluoro-3-(trifluoromethyl)phenylacetyl)-L-alaninyI I -amino-7- methyl-S ,7-dihydro-6H-dibenz[b,djazepin-6-one 5-{N ,6-trifluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5 ,7- dihydro-6H-dibenz[b ,d~azepin-6-one '-(4-fluoro-2-(trifluoromethyl)phenylacetyl)-L-alaninyl}I-amino-7- methyl-S ,7-dihydro-6H-d ibenz[b azepin-6-one N' -(2-fluoro-4-(trifluoromethyl)phenylacetyl)-L-alaninyl)}-amino-7- methyl-S ,7-dihydro-6H-dibenb dlazepin-6-one 879 -(4-hydroxyphenylacetyl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro-6H- dibenzb dlazepin-6-one -(4-methoxyphenoxyacetyl)-L-alaninyl)}-amino-7-methyl-5 7-dihydro- 6H-dibenzb,d]azepin-6-one -(2-methoxyphenylacetyl)-L-alaninyl) -amino-7-methyl-5 ,7-dihydro- 6H-dibenzb, dlazepin-6-one N' -(2-bromophenylaceryl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro-6H- dibenb djazepin-6-one '-(4-benzyloxyphenoxyacetyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro- 6H-dibenz~b ,dlazepin-6-one -(4-hydroxyphenoxyacety)-L-alaniny}-amino-7-methyl-5,7-dihydro- 6H-dibenb dlazepin-6-one -(levulinyl)-L-alaninyl} -amino-7-methyl-5 ,7-dihydro-6H- dibenz[b,djazepin-6-one 5-f{N'-(2-hydroxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro-6H- dibenzlb dlazepin-6-one N' ,4-dimethoxyphenylacetyl)-L-alaninyl }-amino-7-methyl-5 ,7- dihydro-6H-dibenz[b ,djazepin-6-one *o -(3-(4-methoxybenzoyl)propionyl)-L-alaninyl}-amino-7-methyl-5 ,7- 30 o dihydro-6H-dibenz[b ,d]azepin-6-o ne {N '-(3-(4-phenylbenzoyl)propionyl)-L-alaninyl }-amino-7-methyl-5,3- dihydro-6H-diberiz[b ,dlazepin-6-one 5-{N'-(3-hydroxyphenylacetyl)-L-alaninyl}-anino-7-methyl-5 ,7-dihydro-6H- dibenz[b,dlazepin-67one 00 5-f{N'-(N-acetyl-N-phenylglycinyl)-L-alaninyl} -amino-7-niethyl-5 ,7-dihydro- 6H-dibenzb,d] azepin-6-one 0: 0. 5- -(thiophene-3-acetyl)-L-alaninyl} -amino-7-methyl-5 ,7-dihydro-6H- dibenb d~azepin-6-one .00.5-{N'-(6-phenylhexanoyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro-6H- dibenz~b ,dlazepin-6-one -(cyclohexanebutyryl)-L-alaninyl} -amino-7-methyl-5 ,7-dihydro-6H- diberizb ,dliazepin-6-one
880-- N' S-trifluorophenylacety)-L-alaniny} I aino-7-methy-5 ,7- dihydro-6H-dibenz[b dlazepin-6-one N' -(2,45tiloopeyaey)L-lnnl-mio7mty-,7- dihydro-6H-dibenz(b,djazepin-6-one N'-(vinylacetyI)-L-alaninyI}-amino-7-methljs, 7-dihydro-6H- dibenz[b, djazepin-6-one 3 -methy Ithiopropiony) -L-aaniny Iamino7 -mehy I -5 ,7-d ihydro- 6H dibenz[b dazepin-6-one {N'-(3-nitrophenylacetyl)-L-alaninyl 1)-amino- 7-methyl-5 ,7-d ihyd ro-6}{- dibenz[b dazepin-6-one {N '-(n-tert-butylsuccinamyl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro-6H- dibenz[b ,d]azepin-6-one 5-{N'-(4-bromophenylacetyl)-L-alaniny] }-amino-7-methyl-5 ,7-dihydro-6H- dibenz~b,d]azepin-6-one 5-f{N'-(3-(4-fluorobenzoy)propiony)-L-aany-aino7-methyls 7- dihydro-6H-dibenz[b ,dlazepin-6-one 25 5- -(o-chlorophenoxyacetyl)-L-alaninyl }-arnino-7-methyl 7-dihydro-6H- dibenb d]azepin-6-one N' -(p-tolylaceyl)-L-alaninyl} -amino-7-methyl-5 ,7-dihydro-6H- dibenz[b ,d]azepin-6-one '-(m-tolylacetyl)-L-alaninyl)}-amino-7-methyl-5 ,7-dihydro-6H- dibenz[b ,dlazepin-6-one ,4-dichlorophenylacetyl)-L-alaninyl)}-amino-7-methyl-5 .7-dihydro- :35 6H-dibenzb,d~azepin-6-one 4 -chlorophenoxyacetyl)-L-alaninyl}-amino.7methyl-5,7-dihydro-6H- dibenz[b, dlazepin-6-one 40 5-{N'-(3-methylphenoxyacetyl)-L-alaninyl-amino.7metl-5 .7-dihydro- 6H-dibenzb, dlazepin-6-one {N '-(4-isopropylphenoxyacetyl)-L-alaninyl) -amino-7-methyl-5 ,7-dihydro- 6H-dibenzb,dJ azepin-6-one N' -(4-phenoxyphenylacetyl)-L-alaniny 1)-amino-7-methyl-5, 7-dihydro-6H dibenz[b ,djazepin-6-one 881 }-ainino-7-methyl-5,7-dihydro-6H- dibenzflb d]azepin-6-one 4 -ethoxyphenyacey)-L-Ianiny1-aino-7-methy1-5,7-dihydro-6H dibenzb.d]azepin-6-one ,5-dimethoxyphenylacetyl)-L-alaninyl }-arnino-7-methyl-5, 7- dihydro-6H-dibenz[b ,dJ azepin-6-one 5-{N'-(o-tolylacetyl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro-6H- dibenz[b,d] azepin-6-one ,3-diphenylpropiony1)-L-alaninyI}-amino-7-methyI-5 ,7-dihydro-6H- dibenz[b,d] azepin-6-one '-(3-phenoxypropionyl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro-6H- dibenzb ,dlazepin-6-one 4 -(trifluoromethyl)phenylacetyl)-LaannyI-amino7methyls.7- dihydro-6H-dibenzb,d] azepin-6-one -((4--methylphenoxy)acetyl)-L-alaninyl} -amino-7-methyl-5 .7-dihydro- 6H-dibenzjb ,d]azepin-6-one 5-{N '-(2-phenoxyphenylacetyl)-L-alaninyl)}-amino-7-methyl-5 ,7-dihydro-6H- dibenz[b ,d]azepin-6-one '-(3-phenoxyphenylacetyl)-L-alaninyl} -amino-7-methyl-5 ,7-dihydro-6H- dibenz[b ,dlazepin-6-one ,4-dichlorophenoxyacetyl)-L-alaninyl }-amino-7-methyl-5 .7-dihydro- 6H-dibenz[b,d] azepin-6-one '-(4-fluorophenoxyacetyl)-L-alaninyl-amino-7-methyl.s,7-dihydro-6H- :35 dibenz[b,d]azepin-6-one .4,5-trimethoxyphenylacetyl)-L-alaninyl}-amino-7methyl.s 7- dihydro-6H-dibenz~b,d] azepin-6-one 40 5- {N ,4-dichlorophenylacetyl)-L-alaninyl -amino-7-methyl-5 ,7-dihydro- 6H-diberiz[b ,dlazepin-6-one N' -(4-thianaphthenacetyl)-L-al aninyl -amino-7-methyl-5 7-dihydro-6H dibenzfb azepin-6-one 5-{(N'-(methoxyacety1) -L-alaninyl1) -amino-7 -methy1- 5 .7-d ihydro-6H- dibenz[b,d]azepin-6-one 882 N '-(ethoxyacetyl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro-6H- dibenz~b dlazepin-6-one N '-(phenoxyacetylI)- L-alaninyl1)-amino- 7-methyl- 5, 7-dihydro-6H- dibenz~b.dlazepin-6-one {N -methoxyphenoxyacetylI)-L-alaninylI}I-amino- 7-methyI- 5 ,7-diliydro- 6H-dibenz[b,d] azepin-6-one N'-(4-butoxyphenylacetyl)-L-alaninyl} -amino-7-methyl-5 ,7-dihydro-6H- dibenz[b ,d]azepin-6-one 5-f{N'-(3-(2-methoxyphenyl)propionyl)-L-alaninyl} -amino-7-niethyl-5 ,7- dihydro-6H-dibenz~b ,d]azepin-6-one N ,N-dimethylsuccinamyl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b 41 azepin-6-one N' ,4-inethylenedioxyphenyl)propionyl)-L-alaninyl }-amino-7 methyl-S ,7-dihydro-6H-dibenz[b azepin-6-one {N '-(2-chloro-6-fluorophenylacetyl)-L-alaninyl }-amino-7-methy 1-5,7- dihydro-6H-dibenb ,d]azepin-6-one 5-f{ N 5-difluorophenylacetyl)-L-alaninyl)}-amino-7-methyl-5 ,7-dihydro- 6H -dibenz[b azepin-6-one 5-f N' -(pentafluorophenoxyacetyl)-L-alaniny I}I-amino- 7-methyl1-5,7 7-dihydro- 6H-dibenz[b,djazepin-6-one ,5-bis(trifluoromethyl)phenylacetyl)-L-alaninyl}-amino-7-methy 1- ,7-dihydro-6H-dibenzllb,d]azepin-6-one ,5-dimethylphenoxyacetyl)-L-alaninyl }-amino-7-methyl-5 ,7- dihydro-6H-dibenz[b,d]azepin-6-one N '-(4-chlorophenylacetyl)-L-alaninyl} -amino-7-methyl-5 ,7-dihydro-6H N' -(3-chlorophenoxyacetyl)-L-alaninyl) -amino-7-methyl1-5 ,7-dihydro-6H dibenz[b ,djazepin-6-one '-(benzo[blthiophene-3-acetyl)-L-alaninyl}-amino-7-methyl-5 ,7- dihydro-6H-dibenz[b ,d]azepin-6-one ,5-dimethoxyphenylacetyl)-L-alaninyl} -amino-7-methyl-5 ,7- dihydro-6H-dibenz[b ,d]azepin-6-one 883 .5-dimethylphenylacetyI)-L-alaninyl}-amino-7-methy1. 7-dihydro- 6H-dibenz~b ,dlazepin-6-one N' -(mes ity lacetylI)-L-alaninyl1}-amino- 7-methy 1-5 ,7-dihydro-6H- dibenz[b,d]azepin-6-one N' -(4-biphenylacetyl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro-6H4- dibenz[b ,d]azepin-6-one N'-(N-(tert-butoxycarbonyl)-3-aminopropionyl)-L-alaninyl }-amino-7- methyl-S ,7-dihydro-6H-dibenz[b dlazepin-6-one 5-f{N'-(trans-sylacetyl)-L-alaninyl-amino-7-methyl-5 ,7-dihydro-6H- dibenb azepin-6-one '-(4-acetamidobutyryl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro-6H- dibenzb ,d~azepin-6-one -chlorophenyl)propionyl)-L-alarinyI}I-amino- 7-methy 1-5, 7- dihydro-6H-dibenz[b,d]azepin-6-one 5-{N'-(butyryl)-L-alaninyl}-amino-7-methyl-5 ,7-dihydro-6H- dibenz(b,d]azepin-6-one 25 5- -(trans-3-hexenoyl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro-6F1- dibenz[b azepin-6-one -(5-phenylvaleryl)-L-alaninyl} -amino-7-methyl-5 ,7-dihydro-6H- dibenz[b ,d]azepin-6-one '-(3-(3-methoxyphenyl)propionyl)-L-alaninyl) -amino-7-methyl-5,2- dihydro-6H-dibenz[b ,d]azepin-6-one '-(4-chloro-beta-methylhydrocinnamy])-L-alaninyl)}-amino-7-methyl- :35 5 ,7-dihydro-6H-dibenz[b,djazepin-6-one {N '-(3-(trifluoromethyl)butyryl)-L-alaninyl} -amino-7-methyl-5 ,7-dihydro- 6dibenz[b ,d]azepin-6-one 5-{(N'-(al(phnpoxyezyt royl)-L-alaninyl -amino-7-methyl-5 ,7-r-H dihydro-6H-dibenz[b ,dllazepin-6-one N '-(3-(2-trifluoromethylbenzoylI)propionyl)-L-alaninyl I}-amino-7 -methylI- 5,7 -d ihydro-6H-dibenz~b 41 azepin-6-one 884 -benzoylaniino-3 -pheny I-prop ionyl)>L-alanny I}I-amino- 7-methylI- 7-dihydro-6H-dibenz[b dlazepin-6-one N' 4 -(hydroxyimino)pentanoyl)-L-alaninyl }-amino-7-rnethyl-5 ,7- dihydro-6H-dibenz[b,d]azepin-6-one 5- 4 4 -ethyl-phenoxy)-phenoxy)-acetyl)-L-alaniny I -amino-7-methy I- 7-dihydro-6H-dibenz[b,dlazepin-6-one 3 -BenzoyI-3 -pheny Ipropiony aaniny1 amino7mehy I-5, 7 dihydro-6H-dibenz[b, d] azepin-6-one 4 -(hydroxymethy)phenoxyacety)-LaannyI-aino7mey.5 7- dihydro-6H-dibenz[b dazepin-6-one 4 4 4 -tifluorobuyI)-L-alaninyl) -amino-7methy.5 7-d ihydro-6H dibenz[b,d]azepin-6-one {N isobutyrylarnino-3-phenyl-propionyl-L-alaninyl)}-amino-7-methyl 7-dihydro-6H-dibenz[b azepin-6-one 5-f{N'-((2-methylphenoxy)acetyl)-L-aainyl}-amino7.methyls .7-dihydro- 6H-dibenz[b ,d]azepin-6-one '-(3-(phenylsulfonyl)propionyl)-L-alaninyl }-amino-7-methyl-5 ,7- dihydro-6H-dibenz[b ,d]azepin-6-one '-(4-nitrophenylacetyl)-L-alaninyl} -axnino-7-methyl-5 ,7-dihydro-6H- dibenb ,d]azepin-6-one 5-{N'-(3-ethoxypropionyl)-L-alaninyl}-amino-7-metl-s, 7-dihydro-6H- :35 diberiz[b,d]azepin-6-one ~5-f N' 3-difluoromandelyl)-L-alaninyl)}-amino-7-methyl-5 ,7-dihydro-6H- dibenzb ,d]azepin-6-one :40 6-difluoromandelyl)-L-alaninyl)}-amino-7-methyl-5 ,7-dihydro-6H- *.*.dibenz[b ,d]azepin-6-one 4 -fluoromandelyl)-L-alaninyl-amno-7-methyl-5s,7-dihydro-6H- dibenz[b azepin-6-one ,5-difluoromandelyl)-L-alaniny1-amino7-methy15 ,7-dihydro-6H- dibenz[b ,dI azepin-6-one 885 N -beta-phenylIlactyl)-L-alaniny 1)-amino-7-methyl -5,7-d ihydro-6H- dibenz jb .djazepin-6-one }-amino-7-merthyl-5 ,7-dihydro-6H-dibenz jb ,djazepin-6- one N' -(p-chloromandelyl)-L-alaninyl)}-amino-7-niethyl-5 ,7-dihydro-6H- dibenz[b,djazepin-6-one 5- -(I-alpha-hydroxyisocaproyl)-L-alaninyl }-axnino-7-methyl-5, 7-d ihydro- 6H-dibenz[b azepin-6-one N' -(4-bromomandelyl)-L-alaninyl)}-aniino-7-methyl-5 ,7-dihydro-6-- dibenz[b ,dljazepin-6-one +)-lactyl)-L-alaninyl}-amino-7-methyl-s ,7-dihydro-6H- dibenz [b,d]azepin-6-one '-(d-3-phenylacetyl)-L-alaninyl }-amino-7-methyl-5 ,7-dihydro-6H- dibenz[b ,d]azepin-6-one 5-f{N'-(5-methylhexanoyl)-L-alaninyl)-amino-7-methyl- 7-dihydro-611- dibenz[b ,d]azepin-6-one ,5-difluorophenylacetyl)-L-methioninyl }-amino-7-methyl-5 ,7- dihydro-6H-dibenz[b ,dlazepin-6-one ,5-difluorophenylacetyl)-L-2-phenylglycinyl}-axnino-7-methyl-s ,7- dihydro-6H-dibenz[b azepin-6-one ,5-difluorophenylacetyl)-L-leucinyl)}-amino-7-methyl-5 ,7-dihydro- 6H-dibenz[b,d]azepin-6-one ,5-difluorophenylacetyl)-L-2-cyclohexylglycinyl} -amino-7-methy 1- 35 5 ,7-dihydro-6H-dibenz[b ,d~azepin-6-one 5-{N 5-difluorophenylacetyl)-L-threoninyl} -amino-7-methyl-5 ,7-dihydro- 6H-dibenz(b ,d~azepin-6-one 7. :40 5-f{ N 5-difluorophenylacetyl)-L-alpha-(2-thienyl)glycinyl }-amino-7- methyl-S ,7-dihydro-6H-dibenz[b azepin-6-one {N '-(2-thiopheneacetyl)-L-methioninyl)}-amino-7-methyl-5 ,7-dihydro-6H- dibenz[b ,d]azepin-6-one -(2-thiopheneacetyl)-L-2-phenylglycinyl} -amino-7-methyl-5 ,7-dihydro- 1 6H-dibenz[b ,dlazepin-6-one 886 thiopheneacetyLI)- L-leuciny 1)-amino 7methy 1 -57-dihydro-6H- dibenz[b, dlazepin-6-one 2 -thiopheneacetyl)-L-2-cyclohexylglycinyl} -aino- 7-methyl.1 5,7 dihydro-6H-dibenz~b .d~azepin-6-one N'-(2-thiopheneacetyl)-L-threoninyl)}-aznino-7-methy 1-5, 7-dihydro-6H- dibenz[b ,d]azepin-6-one 5-{N'-(2-thiopheneacey)-L-apha(2-thieny)glyciny }-amino-7-methyl-5 ,7- dihydro-6H-dibenz[b dazepin-6-one {N '-(isovalerylI)-L-methioninyl) -amnino- 7-methyl-5 7-d ihydro-6H- dibenz[b dazepin-6-one S-{N '-(isovaleryl)-L-2-phenylglyciny)-amino7methyl..s, 7-dihydro-6H- dibenz~b dazepin-6-one -(isovaler-yl)-L-Ieucinyl }-amino-7-methyl-5 ,7-dihydro-6H- dibenz[b,dlazepin-6-one '-(isovaleryl)-L-2-cyclohexylglycinyl }-amino-7-methyl-5 ,7-dihydro-6H- dibenz[b,d] azepin-6-one 25 5-{N '-(isovaleryl)-L-threoninyl} -aniino-7-methyl-5 ,7-dihydro-6H- dibenz[b d)azepin-6-one {N '-(isovaleryl)-L-alpha-(2-thienyl)glycinyl)}-axnino-7-methyl-5,7-dihydro- 6H-dibenz[b ,d~azepin-6-one '-(phenylacetyl)-L-methioninyl }-arnino-7-methyl-5 ,7-dihydro-6H- dibenz[b,d]azepin-6-one 5-{N'-(phenylacetyl)-L-2-phenylglycinyl }-amino-7-methyl-5 ,7-dihydro-6H- :35 dibenzb,d]azepin-6-one N' -(phenylacetyl)-L-Ieucinyl }-axnino-7-methyl-5 ,7-dihydro-6H- dibenz~b ,d]azepin-6-one :40 5-{N '-(phenylacetyl)-L-2-cyclohexylglycinyl-amino7mefiyl-5, 7-dihydro- 6H-dibenz~b,d] azepin-6-one -(phenylacetyl)-L-threoninyl }-aznino-7-methyl-5 ,7-dihydro-6H- dibenz[b ,d)azepin-6-one N' -(phenylacetyl)-L-alpha-(2-thienyl)glycinyl} -aniino-7-methyl-5 ,7- dihydro-6H-dibenb azepin-6-one; PAOPER\Ma62(Xt2W)7-8 SPtpO %p7OX7 oait, 6 to 147.doc-2O 5i2 -887- and pharmaceutically acceptable salts thereof. The compound according to Claim 57, wherein T is a bond covalently linking R 1 to -CX'X". 86. The compound according to Claim 85, wherein n is 1. 87. The compound according to Claim 86, wherein p is 1. 88. The compound according to Claim 87, wherein R 2 is alkyl. 89. The compound according to claim 88, wherein X' and X" are hydrogen. 90. The compound according to claim 89, wherein R' is alkyl. 91. The compound according to Claim 90, wherein R' is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, n-butyl, n-pentyl, and isovaleryl. 92. The compound according to Claim 88, wherein R 1 is aryl. 93. The compound according to Claim 92, wherein R' is selected from the group consisting of phenyl wherein the substituted phenyl has 1 to 3 substituents independently selected from the group cinsisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and 25 thioalkoxy. 94. The compound according to Claim 88, wherein X' is hydrogen and X" is hydroxy. The compound according to Claim 94, wherein R'is alkyl. The compound according to Claim 95, wherein R' is selected from the group P:\OPER\Ma1'O02\57(XJ7-98 sp\r5s7 0 07 claim 86 to 147.dom62A1M5A2 -888- consisting of methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, n-pentyl, and isovaleryl. 97. The compound according to Claim 95, wherein R' is aryl. 98. The compound according to Claim 97, wherein R' is selected from the group consisting of phenyl and substituted phenyl wherein the substituted phenyl has 1 to 3 substituents independently selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy. 99. The compound according to Claim 88 wherein the cyclic group defined by W- C(H)pC(=X) is selected from the group having the formulas: (R)w (V ON 0 Rb 0 .M t (Ra)w Mt -N R PA\OPER\Mal\2(X)2\57tM)7-98 spo~ooptU57867 dIitns 86 to 147.dloc-412M.W62 -889- (Ra)W Mt) RR y N MVt V t Ra Rb RC N R 0 MVt MVt N N b b* R R /0 B 00.0* 00 N N \7N P:\OPERWA2L002\57007-93 "pNnspl\70O7 oaimn, 86 to 147.do-02A)S/2 -890- wherein A-B is selected from the group consisting of alkylene, alkenylene, substituted alkylene, substituted alkenylene and Q' is oxygen or sulfur; each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl; R a is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl, cyano, halo; Rb is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl, and substituted cycloalkyl; t is an integer from 0 to 4; t' is an integer from 0 to 3; and w is an integer from 0 to 3. 100. The compound according to Claim 88 wherein said cyclic group is selected from the group having the formulas: R 0 N R b 1 (Ra) w N Sb 0 Rb PAOPER\MI(X)2Z57(X7-9S spo6cspW~7)7 cLhimo 86 to 147.dwoc4)2j5A)2 891 00 0 sees roe, 0 PA~OPERWAM3760SO7-9S tpjXraplS7007 clim~ 96 to 147,doc-02MMA) -892- wherein Rb, V, Q, t and w are as defined in Claim 99. 101. The compound according to Claim 88 wherein said cyclic group is a lactam selected from the group having the formulas: P:%OPER\MaR\2OO2\571X)7-98 spe~spI\7O) 7 daunt 86 to 147.d=)2t5fi2 893 NN R Rb R 0* R N\ Rb P:\OPERW\aU2U~7(X7-98 spe\ropI\57OO07 cbiot M to 147.doc-O2A)SA)2 894 is alkyl. P:\OPER\M[U(X)257OO7-98 spcooopI\57(XJ7 chint 96 to 147.doc4)2A)SA)2 -895- 102. The compound according to Claim 101, wherein X' and X" are hydrogen. 103. The compound according to Claim 102, wherein R' is alkyl. 104. The compound according to Claim 103, wherein R' is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, n-butyl, n-pentyl, and isovaleryl. 105. The compound according to Claim 104, wherein R 2 is methyl. 106. The compound according to Claim 105, wherein Rb is selected from the group consisting of methyl, ethyl, isopropyl, and isobutyl. 107. The compound according to Claim 106, wherein Rb is methyl. 108. The compound according to Claim 102, wherein R' is aryl. 109. The compound according to Claim 108, wherein R' is selected from the group consisting of phenyl and substituted phenyl wherein the substituted phenyl has 1 to 3 20 substituents independently selected from the group consisting of alky, alkoxy, halo, cyano, nitro, trihalomethyl, and tioalkoxy. 110. The compound according to Claim 109, wherein R 2 is methyl. 111. The compound according to Claim 110, wherein R b is selected from the group consisting of methyl, ethyl, isopropyl, and isobutyl. 112. The compound according to Claim 111, wherein Rb is methyl. 3. The compound according to Claim 101, wherein X' is hydrogen and X" is hydroxy. P:XOPERUa\2OO(X2\37OO7-98 spe\rwoplI\57X) e7 dlo 86 to 147.dom)2A)SA)2 -896- 114. The compound according to Claim 113, wherein R' is alkyl. 115. The compound according to Claim 114, wherein R 1 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, n-butyl, n-pentyl, and isovaleryl. 116. The compound according to Claim 115, wherein R 2 is methyl. 117. The compound according to Claim 116, wherein R b is selected from the group consisting of methyl, ethyl, isopropyl and isobutyl. 118. The compound according to Claim 117, wherein Rb is methyl. 15 119. The compound according to Claim 113, wherein R' is aryl. 120. The compound according to Claim 119, wherein R' is selected from the group consisting of phenyl and substituted phenyl wherein the substituted phenyl has 1 to 3 substituents independently selected from the group consisting of alky, alkoxy, halo, cyano 20 nitro, trihalomethyl, and thioalkoxy. 121. The compound according to Claim 120, wherein R 2 is methyl. 4* 122. The compound according to Claim 121, wherein Rb is selected from the group consisting of methyl, ethyl, isopropyl and isobutyl. 123. The compound according to Claim 122, wherein Rbis methyl. p24. The method according to any one of Claims 1 to 3, wherein T is a bond and n is 1 dpis 1. P:\OPERM[L(XO2\57(X)7-98 spc\p\57(X)7 claim 86 to 147.doC4)26)5/02 -897- 125. The method according to Claim 124, wherein R 2 is alkyl. 126. The method according to Claim 125, wherein X' and X" are hydrogen. 127. The method according to Claim 126, wherein R' is alkyl. 128. The method according to Claim 127, wherein R' is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, n-butyl, n-pentyl and isovaleryl. 129. The method according to Claim 126, wherein R' is aryl. 130. The method according to Claim 129, wherein R 2 is selected from the group 15 consisting of phenyl and substituted phenyl wherein the substituted phenyl has 1 to 3 substituents independently selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy. 131. The method according to Claim 125, wherein X' is hydrogen and X" is hydroxy. 132. The method according to Claim 131, wherein R' is alkyl. 133. The method according to Claim 132, wherein R' is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, n-butyl, n-pentyl and isovaleryl. 134. The method according to Claim 131, wherein R'is aryl. 135. The method according to Claim 134, wherein R' is selected from the group isting of phenyl and substituted phenyl wherein the substituted phenyl has 1 to 3 P:%OPER\MaI\2f3()2\57(398 l~p\7007 climrn 861 to47.doc4)2A15/02 -898- substituents independently selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and tioalkoxy. 136. The method according to Claim 124, wherein the cyclic group defined by W- C(H)pC(=X) is selected from the group haying the formulas: P:\OPERM,1\2f)2\5i7(X)7-98 spc~mPW7OO?7 clim, 86 to 147.dloc-02MM18 -899- MVt 0 N 0 (Ra) (a..-Vt Mt (RaR,, N N aR )t V)VMt' SRaI P.\OPER\MaI\2002\5700198 spemsp1\37007 claims 86 to l47.dow-O2A)5A) -900- Rb Rc I N N N Rb R A- B N N R c R c wherein A-B is selected from the group consisting of alkylene, alkenylene, substituted alkylene, substituted alkenylene and Q' is oxygen or sulfur; each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like; Ra is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; Rb is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, heteroaryl, heterocyclic and the like; Rc is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl, and substituted cycloalkyl; t is an integer from 0 to 4; t' is an integer from 0 to 3; and w is an integer from 0 to 3. The method according to Claim 124, wherein said cyclic group is selected from the P:AOPERWtW2(XtZt7007-98 spc~respJt57007 choi=t 96 to 147.doc-021051U2 901 group having the formulas: (Ra). Rb 0 (Ra), (Ra). R b MVt MVt 0* R R0 PAkOPER\MIU.2OO2\37(XO7-98 trsp I\57007 chti=t 86 to 147.dc-)2A)42 902 Rb S S S. S S. S 5555 wherein Ra, Rb, V, Q, t and w are as defined in Claim 136. PAOPERVMUMMO2~7007-98 qn~ooI\57W)7 claims 861to l47.dom-82A)5A)2 903 138. The method according to Claim 136, wherein said cyclic group is a lactam selected from the group having the formulas: a. P:\OPER\Mad\2OO2Z57(XO7.9H spo 6 mp\ 57 (X) 7 cIahm 86 to 147.doc-02Al5A)2 904 0 0 t Rb Rb 0 0* 0 0* F CH 3 CH 3 P:\OPERkMaoI207007-98 spc\mV6IU5700 7 clim~ 86 wo 147.doc.02A)5/02 905 CH 3 N Rb 0 Rb *I 00 N *N R b N Rb PAOPER\4o8282\S7007-98 ,oCVospI%57007 claims 86 to 147.doc4)VOSA2 -906- 139. The method according to Claim 138, wherein X' and X" are hydrogen, R' is alkyl, R 2 is methyl, and Rb is selected from the group consisting of methyl, ethyl, isopropyl, and isobutyl. 140. The method according to Claim 139, wherein R' is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, n-butyl, n-pentyl and isovaleryl. 141. The method according to Claim 138, wherein X' is hydrogen and X" is hydroxy, R' is alkyl, R 2 is methyl, and R b is selected from the group consisting of methyl, ethyl, isopropyl, and isobutyl. 142. The method according to Claim 141, wherein R' is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, n-butyl, n-pentyl and S. 15 isovaleryl. 143. The method according to Claim 138, wherein X' and X" are hydrogen, R' is aryl, R 2 is methyl and Rb is selected from the group consisting of methyl, ethyl, isopropyl, and isobutyl. 144. The method according to Claim 143, wherein R 1 is selected from the group .o consisting of phenyl and substituted phenyl wherein the substituted phenyl has 1 to 3 substituents independently selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy. 145. The method according to Claim 138, wherein X' is hydrogen, X" is hydroxy, R' is aryl, R 2 is methyl and Rb is selected from the group consisting of methyl, ethyl, isopropyl and isobutyl. 146. The method according to Claim 145, wherein R' is selected from the group consisting of phenyl and substituted phenyl wherein the substituted phenyl has 1 to 3 P:\OPER\MI2237(X7-98 spekrompI -570o7 climo 86 to l47.doc-02AJ3102 907 substituents independently selected from the group consisting of alkyl, alkoxy, halo, cyano, 'nitro, trihalomethyl, and thioalkoxy. DATED this 2nd day of May, 2002 Elan Pharmaceuticals,Inc AND Eli Lilly and Company By DAVIES COLLISON CAVE Patent Attorneys for the Applicants
AU57007/98A 1996-12-23 1997-12-22 Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting beta-amyloid peptide release and/or its synthesis by use of such compounds Ceased AU749658C (en)

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US78002596A 1996-12-23 1996-12-23
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PCT/US1997/022986 WO1998028268A2 (en) 1996-12-23 1997-12-22 CYCLOALKYL, LACTAM, LACTONE AND RELATED COMPOUNDS AS β-AMYLOID PEPTIDE RELEASE INHIBITORS

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